Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer
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Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
*Phone: (650) 467-3214. E-mail: [email protected]
Copyright © 2016 American Chemical Society
Supporting Info (1)»
Abstract
In addition to each of the factors that govern the identification of a successful oncology drug candidate, drug discovery aimed at treating neurological cancer must also consider the presence of the blood–brain barrier (BBB). The high level of expression of efflux transporters (e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp)) at the BBB limits many small molecules from freely reaching the brain, where neurooncologic malignancies reside. Furthermore, many of the targets identified for the potential treatment of central nervous system (CNS) malignancies suggest that kinase inhibitors, capable of penetrating the BBB to reach their target, would be desirable. This Perspective discusses the unmet need for neurooncology treatments, the appeal of kinase targets in this space, and a summary of what is known about free brain penetration of clinical inhibitors of kinases that are of interest for the treatment of brain cancer.
Background
ARTICLE SECTIONS
Neurooncology encompasses the study of tumors that originate in the brain (e.g., glioblastoma multiforme (GBM)) as well as brain metastases. In 2015, it was anticipated that more than 21 000 new cases of malignant brain and central nervous system (CNS) cancers would be diagnosed in the United States that year.(1) Among malignant brain tumors, the most common is GBM which has an associated poor prognosis (3-year survival rate 3–5%).(2) Despite the apparent unmet medical need, there has been little progress in developing new treatments for GBM. Most evaluations of chemotherapeutics in GBM have failed. Currently, the alkylating agents temozolomide (approved 2005) and the carmustine-based Gliadel wafer (approved 1996) are the only chemotherapeutics that are FDA approved for the treatment of newly diagnosed GBM. Other neurological cancers have similarly limited drug treatment options.
In addition to the need for more treatment options for primary brain tumors, metastasis of tumors to the CNS occurs from as many as 40% of peripheral tumors, with well over 100 000 cases per year.(3) When a kinase inhibitor is used for the treatment of peripheral disease, such CNS metastasis is a risk as a mechanism of emergent resistance if that inhibitor is not freely CNS penetrant. In this scenario, treatment of a tumor with drug is effective until disease progression occurs in the CNS, where drug concentrations are limited. As an example of the significance of the challenge presented by resistance due to CNS metastases, 14% of patients with HER2-positive breast cancer treated with pertuzumab had first evidence of disease progression due to CNS metastasis, evidently as a result of the inability of pertuzumab to cross the blood–brain barrier (BBB).(4) Unfortunately, as discussed below, this scenario is not limited to HER2-positive disease treated with a therapeutic antibody but also happens with numerous FDA approved small molecule kinase inhibitors that do not penetrate the CNS. For CNS metastases, prognosis is generally poor and chemotherapy is useful only in limited settings,(5) furthering the unmet need for new chemotherapeutics for malignancy in the CNS.
While primary brain tumors and brain metastases are distinct disease manifestations and may require targeting different drivers of disease, for the medicinal chemist, the approach to treating each of these indications requires the same considerations of the BBB, which typically limits small molecule penetration to the CNS where brain tumors reside. Furthermore, for both primary and secondary brain tumors there is biological rationale to develop BBB penetrating kinase inhibitors.
While there have been 32 kinase inhibitors approved for the treatment of cancers that reside outside the CNS, no kinase inhibitor has been approved for the treatment of primary CNS tumors, while alectinib (61) has recently received accelerated approval to treat patients including those with brain metastases. One reason for the lack of approved kinase inhibitors for treating brain tumors is that in order to effectively treat brain tumors, the kinase inhibitor must be capable of reaching its target. Therefore, the kinase inhibitor must effectively cross the BBB. As will be discussed below (and included as Supporting Information), the majority of approved kinase inhibitors and kinase inhibitors that have advanced to clinical study have no report of CNS penetration, reportedly limited CNS penetration, or CNS penetration that is expected to be limited due to the action of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp).
When considering potential therapeutics for the treatment of brain cancer, it is frequently asserted that because of disruption of the BBB by primary tumors or metastases in the brain, consideration of the BBB is not relevant. However, while it may be true that a tumor can disrupt the BBB, it generally does so just partially and significant literature reports indicate the importance of the BBB in limiting drug penetration to its intended target even when a tumor causes such partial disruption.(6) Additionally, GBM in particular is noted to grow in a diffuse manner in which a significant portion of the tumor grows behind an intact BBB, and so without effective drugs that are capable of freely crossing that barrier the tumor progresses.(7) That GBM grows in such a manner so as to remain behind an intact BBB punctuates the need for small molecules to be able to penetrate that barrier if they are to have potential to effectively treat that disease.
With an understanding of the importance of free BBB penetration for drugs targeting brain cancer, neurooncology medicinal chemistry programs have much in common with programs for other CNS diseases. Fortunately, in recent years there has been a much improved appreciation for the requirement to achieve sufficient free drug concentration in the brain, if that is where the target resides. A recent Perspective provides an excellent review of the concepts of free brain penetration that are essential to CNS and neurooncology programs alike and pertinent to the remainder of the discussion within.(8) Succinctly, it is important to note that it is critical that kinase inhibitors that are intended to treat brain tumors achieve therapeutically beneficial free drug concentrations in the brain. Indeed, a recent conference on CNS cancer drug discovery and development emphasized the need for neurooncology programs to focus on achieving free brain penetration.(9) To assess in preclinical studies whether effective therapeutic concentrations of a molecule cross the BBB, and therefore whether it has a realistic chance of achieving efficacy by the intended mechanism, some assessment of free brain or, as a surrogate, cerebral spinal fluid (CSF) concentrations is needed.(8) To assess the extent to which a small molecule freely penetrates the BBB (as opposed to just achieving a target free concentration in the brain), a comparison of free brain or CSF concentrations to free plasma concentrations is needed (Kp,uu). It is worth noting here that in the discussion of free brain penetration of clinical kinase inhibitors found below, the target therapeutic concentration is not often available, and so an assessment of free CNS penetration (Kp,uu or free brain-to-free plasma concentration ratios), where available, is utilized for an assessment. Where such values were available, we considered values of <0.1 to be low and evidence of significant limitation to free BBB penetration, whereas values of >0.3 demonstrate a significant degree of free CNS penetration.
In principle, therapeutic free concentration of drug might be able to penetrate the BBB even with very low Kp,uu values. In order for this to occur, however, there would need to be a corresponding increase in systemic exposure that might increase risk of unintended side effects. To illustrate, a kinase inhibitor with a Kp,uu of 0.1 would require 10 times the sytemic exposure to achieve a therapeutic benefit in the brain compared to a kinase inhibitor equivalent in all aspects except for a Kp,uu of 1.0. When targeting CNS disease, then, the importance of maximizing Kp,uu is a significant consideration and likely to impact the safety/tolerability of a molecule at doses required to achieve therapeutically beneficial free concentrations in the CNS.
With an understanding of the importance of achieving free CNS penetration with molecules intended for the treatment of brain cancers, a paramount requirement for achieving significant free drug concentrations behind the BBB is that the small molecules are not strong substrates of P-gp or Bcrp, efflux transporters highly expressed at the BBB.(8, 10) Small molecules that are significant substrates of P-gp are anticipated to have limited free CNS penetration, and in the discussion of clinical kinase inhibitors below, molecules that are reported to be P-gp substrates are suggested to likely have limited CNS penetration.
For medicinal chemists interested in kinase inhibitors to treat brain cancer, avoidance of P-gp transport must be a focus so as to maximize Kp,uu. Considerations in the design of kinase inhibitors (or any small molecule) to limit transporter mediated efflux include a number of physicochemical properties that can be prospectively calculated. Among the most critical properties to consider are the reported correlations between topological polar surface area (TPSA) and/or the number of hydrogen bond donors (HBD) and the likelihood of P-gp mediated efflux.(8) ATP-competitive small molecule kinase inhibitors generally employ hydrogen bonding interactions with the hinge of the kinase, and oftentimes multiple hydrogen bond donors are utilized.(11)
As a result of the common use of frequent hydrogen bond donors within kinase inhibitors, overcoming the physicochemical property restraints that predict efflux while maintaining other desirable attributes of kinase inhibitors, including potency, is a challenge. Indeed, a comparison of the median values of physicochemical properties of 119 CNS approved drugs(12) with those for the 34 kinase inhibitors approved for clinical use (all indications) reveals significant disparities (Table 1). Whereas CNS drugs have a median value of 1 HBD, approved kinase inhibitors have 2. Additionally, approved kinase inhibitors have a median TPSA value double that of approved CNS drugs. Kinase inhibitors also tend to have significantly higher MW and lipophilicity than CNS drugs.
Table 1. Comparison of Median Values of Physicochemical Properties for Kinase Inhibitors Approved for Clinical Use and 119 Drugs Approved for CNS Indications
For more than 30 years, kinase inhibitors have been the focus of significant pharmaceutical pursuit and the appeal of kinase inhibitors as potential therapeutics extends to the treatment of brain tumors and metastases.(14) While the nature of kinase inhibitors, particularly ATP competitive versions, may have some constraints on physical properties to achieve potency that are contrary to what is typical for CNS drugs, realizing potent kinase inhibitors that are capable of significant free brain penetration is possible. However, free brain penetration has not been a design consideration for many kinase inhibitor programs and in some cases may have been intentionally avoided.(15)
Even when intentionally seeking potent and freely BBB penetrant kinase inhibitors, there are, of course, limitations to available in vivo brain cancer disease models in which such molecules can be studied and none “fully reflects human gliomas.”(16) As an example, the U87 model of glioblastoma is a frequently studied GBM model used in orthotopic mouse xenograft studies. The use of the U87 model to assess whether or not a molecule has potential in the treatment of brain cancer is limited, however, as it is known to maintain a highly disrupted BBB, not relevant to clinical disease, and not to grow in the diffuse manner observed in human patients in which the tumor invades healthy brain with an intact BBB.(17) For this reason, the U87 and potentially other models may overestimate the likelihood that an agent may provide therapeutic benefit in human GBM patients. To understand whether the drug is capable of reaching its target in brain tissue, an evaluation of free brain-to-plasma ratios, free brain concentrations, change in brain concentration between wild-type mice and transporter knockout mice, or at least assessment of whether it is a substrate of P-gp or Bcrp is desirable.
The basis for the interest in kinase inhibitors to treat brain tumors begins with the underlying biology of CNS malignancy. In the following sections, individual kinase targets with relevance in CNS malignancy are introduced. In many cases kinase inhibitors have been studied in clinical trials of patients with brain tumors or metastases without success. However, in many of those cases limited CNS penetration of the kinase inhibitor may have contributed to a lack of efficacy. We identify clinical kinase inhibitors for the kinase targets, and within each section on a given kinase target, available data related to brain penetration of any clinical inhibitors of that target are summarized. In the few cases where BBB penetrating inhibitors of a kinase target for brain cancer are reported, the medicinal chemistry efforts leading to this profile are discussed. Ultimately, we summarize whether or not clinical brain penetrant inhibitors of kinase targets of interest for neurooncology are available. Finally, a comparison of the physical properties of clinical CNS penetrant kinase inhibitors for brain cancer with those that have limited CNS penetration reveals remarkable similarity, and disparity from properties of CNS drugs.
VEGFR and PDGFR
ARTICLE SECTIONS
Inhibition of angiogenesis has been established as a beneficial approach to treating cancer, and the potential of this approach to cancer treatment extends to cancers in the CNS.(18) Targeting vascular endothelial growth factor receptors (VEGFRs) has been suggested to be of particular interest for the potential treatment of neurological tumors, as it is a known driver of angiogenesis in CNS tumors and found to be overexpressed in this setting, particularly the highly vascularized GBM.(19) Additionally, platelet derived growth factor receptor (PDGFR), a kinase frequently inhibited by VEGFR inhibitors, has been identified as a potential target for the treatment of GBM due to its high expression in this context.(20) Indeed, at least 14 inhibitors of VEGFR and/or PDGFR have been evaluated for their potential in the treatment of CNS tumors (Table 2), yet an unfortunate few would be expected to freely penetrate the BBB to reach such tumors.
Table 2. Structures and Key Properties for VEGFR and PDGFR Inhibitors Advanced to Clinical Study for Brain Cancera
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
Cediranib (1, Table 2)(21) and pazopanib (2, Table 2)(22) have been studied in phase II and phase III trials in GBM patients but did not show a survival benefit.(23, 24) The diffuse nature of GBM vasculature growth would require effective penetration of brain tissue by the inhibitors to maximize efficacy. However, both cediranib and pazopanib have been reported to be substrates of both P-gp and Bcrp in vitro and these transporters were found to limit brain exposure in mice.(25, 26)
Like cediranib and pazopanib, sunitinib (3),(27) sorafenib (4),(28) nintedanib (5),(29) tivozanib (6),(30) and dovitinib (7)(31) were each ineffective in clinical GBM studies.(32-36) Sunitinib, sorafenib, and nintedanib each are likely to have limited CNS penetration, as they are substrates of P-gp and/or Bcrp, whereas data are not available for tivozanib or dovitinib.(37-39) Furthermore, for sorafenib, another study suggests that patients treated with renal cell carcinoma treated with sorafenib progress due to metastases only observed in the CNS, suggesting a sanctuary from drug due to lack of BBB penetration.(40)
Regorafenib (8, Table 2) demonstrated an effect in a rat model of glioblastoma(41) and, accordingly, advanced to clinical studies for the treatment of GBM.(42) While results are not available, efflux transport may limit free concentrations of regorafenib behind the BBB as the molecule is a substrate of P-gp and Bcrp and in P-gp/Bcrp knockout mice a 5.5-fold increase in brain concentration was achieved when compared to wild type mice at the same time point.(43)
The PDGFR-β, c-KIT, and Flt3 inhibitor tandutinib (9, Table 2) was found to be a substrate of both P-gp and Bcrp, which limits brain exposure in mice.(44) Still, tandutinib was advanced to a phase I clinical trial in patients with GBM. In that study, brain concentrations in 6 patients were determined, and a mean brain-to-plasma ratio (total) in these patients was determined to be 0.33. However, no free brain-to-free plasma ratios or free brain concentration data from subsequent studies have been reported, and so no conclusion can be made about whether or not sufficient target engagment was achieved.(45)
After demonstrating in vivo efficacy in three different orthotopic GBM models in mice,(46) axitinib (10, Table 2)(47) encouragingly demonstrated activity in a phase II study of patients with GBM.(48) However, it remains possible that the extent of benefit derived from axitinib treatment of GBM, where some tumor typically resides behind an intact BBB, may be limited due to the fact that axitinib is a significant substrate of P-gp and Bcrp. This was demonstrated in mouse pharmacokinetic studies in which P-gp/Bcrp knockout mice had 14- and 21-fold increases in brain concentration at 1 and 4 h postdose when compared to wild type mice.(49)
Vandetanib (11, Table 2)(50) and lenvatinib (12, Table 2)(51) are additional VEGFR inhibitors that have advanced to clinical studies to treat GBM(52, 53) despite being reported substrates of P-gp.(54, 55) The ability to achieve efficacious free concentrations in the brain is a concern as P-gp efflux is anticipated to limit drug penetration to portions of tumor where the BBB remains intact.
Whether or not vatalanib (13, Table 2)(56) is a substrate of P-gp or Bcrp in vitro has not been reported, and there are not reports of brain penetration of this molecule either preclinically or clinically. Vatalanib was studied in phase I clinical trials in patients with glioma or GBM, but development of the molecule was halted prior to complete assessment in this patient population.(57)
Cabozantinib (14, Table 2)(58) and brivanib (15, Table 2)(59) stand out among the VEGFR inhibitors discussed here, as they are reported to not be substrates of P-gp transport, suggestive of their potential in the neurooncology setting.(60, 61) To the best of our knowledge, there are no reports of preclinical in vivo studies describing free brain exposure or clinical study results evaluating brivanib for the treatment of CNS tumors. However, consistent with its lack of P-gp transport, cabozantinib has undergone a phase II study for the treatment of GBM and demonstrated some clinical and pharmacodynamic activity.(62)
Among the 15 VEGFR/PDGFR inhibitors discussed here and included in Table 2, just two have been reported to have minimal P-gp mediated efflux, of importance when targeting CNS malignancy. That two, cabozantinib and brivanib, are able to minimize P-gp transport demonstrates that it is possible to achieve with still potent kinase inhibitors and enables assessment of the validity of the hypothesis that inhibiting their targets might be an effective treatment approach for GBM.
EGFR
ARTICLE SECTIONS
The initial success of the epidermal growth factor receptor (EGFR) inhibitors erlotinib (16, Table 3)(63) and gefitinib (17, Table 3)(64) in the treatment of EGFR mutant non-small-cell lung cancer (NSCLC) was followed by the approval of afatinib (18, Table 3)(65) and more recently osimertinib (19, Table 3).(66) In addition to their use in the treatment of NSCLC, erlotinib and gefitinib have been evaluated for the treatment of NSCLC brain metastases that harbor activating mutations of EGFR. Despite some reported benefit of EGFR inhibitor treatment of EGFR mutant NSCLC brain metastases,(67) it is also reported that such molecules are not as effective in the treatment of brain metastases as peripheral metastases, suggesting limited CNS penetration.(68) In this scenario, the inhibitor may be able to effectively treat some, or a portion of, individual metastases where the BBB is compromised, yet lesions behind the BBB continue to grow. Consistent with this theory, PET imaging of 11C-erlotinib showed accumulation of drug in a brain metastasis but not in normal brain tissue. These data suggest that where the BBB is intact, a “sanctuary” for tumor remains.(69) That erlotinib was not capable of freely crossing the BBB was also established in a preclinical model of glioma.(70) Gefitinib, afatinib, and osimertinib have each also been reported to be substrates of both P-gp and Bcrp, and so brain penetration of those EGFR inhibitors is expected to be limited.(71-73) Nevertheless, what free concentration of afatinib that is capable of reaching CNS metastases in EGFR mutant-positive NSCLC has demonstrated benefit clinically.(74)
Table 3. Structures and Key Properties for EGFR Inhibitors Advanced to Clinical Studya
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
The interest in EGFR inhibitors for treating CNS cancer extends beyond brain metastases in NSCLC to GBM treatment. In the most common and aggressive form of brain cancer, GBM, overexpression of EGFR is encountered in approximately 40% of patients and half of these have an associated extracellular mutation of EGFR (variant III).(75) These factors suggest the potential utility of a brain penetrant EGFR inhibitor. Several small molecule EGFR inhibitors, including gefitinib and erlotinib, have been approved for use in EGFR mutant NSCLC but, despite clinical study, have not resulted in approval for the treatment of gliomas.(76)
Investigation of brain penetrant inhibitors of EGFR would therefore be of interest. For rociletinib (20, Table 3)(77) no associated P-gp efflux or brain penetration data have been reported. However, recently there have been two reports of EGFR inhibitors that, while maintaining the quinazoline core of earlier EGFR inhibitors, were reportedly designed to effectively penetrate the BBB to allow for effective treatment of CNS disease. The first, NT113 (21, Table 3), a pan-ERBB inhibitor, demonstrated efficacy in intracranial GBM xeongrafts, including those with high EGFR vIII expression.(78) A limitation in the characterization of 21 is that, while brain-to-plasma ratios are reported, no free brain concentrations or free brain-to-free plasma ratios are reported, limiting the interpretation of just how effectively this molecule penetrates the BBB. Nevertheless, in intracranial GBM xenograft studies, 21 was more efficacious than either erlotinib or lapatinib, potentially indicating some improved degree of effective CNS penetration.
A second recently disclosed quinazoline-based clinical EGFR inhibitor intended to cross the BBB is AZD3759 (22, Table 3).(79) The disclosure of 22 describes the directed effort toward specifically identifying a brain penetrating inhibitor of EGFR for the treatment of CNS tumors, particularly CNS metastases that arise in the course of treatment of EGFR mutant NSCLC. In order to achieve the excellent brain penetration that 22 realizes compared to gefitinib (Figure 1), improving physical properties to reduce transporter mediated efflux was emphasized in the optimization effort. In this case, the number of rotatable bonds had an apparent correlation with efflux, and reduction of rotatable bonds, when compared to gefitinib, resulted in reduced transporter mediated efflux. Furthermore, the fluorine atom of gefitinib was moved to be positioned next to the NH of the aniline in 22 (Figure 1). This positioning allows for intramolecular interaction of the F atom with the NH, thereby “masking” the HBD, commonly associated with increased transporter mediated efflux. The structural modifications relative to gefitinib did not have an apparent detrimental impact on potency, as 22 and gefitinib are reported to have the same potency in a cellular assay employing an L858R EGFR mutant cell line, suggesting its potential in the treatment of NSCLC with EGFR mutant positive brain metastases. The team at AstraZeneca demonstrated the effective penetration of 22 across the BBB in preclinical species by reporting both Kpuu,brain and Kpuu,CSF values that show that the molecule achieves equivalent free concentrations on each side of the barrier in rats. The scientists at AstraZeneca went on to show extensive penetration of 22 into monkey brain in PET imaging studies. 22 also demonstrated remarkable efficacy in an in vivo model of brain metastasis. In this model, 22 clearly differentiates itself from erlotinib, which was not efficacious when administered at the same dose level as 22.
Figure 1
Figure 1. Structural modifications upon gefitinib (17), focused on reducing rotatable bonds and effective hydrogen bond donors, led to the freely BBB penetrating inhibitor of EGFR, 22.
While EGFR has been a long-standing target in GBM, previous molecules have not allowed for clinical conclusion on the validity of the target as transporter mediated efflux does not allow them to freely penetrate the BBB to where tumors reside. The recent emergence of 21 and, particularly, 22 highlights an exciting opportunity to study inhibition of a known driver of a significant percentage of GBM cases and NSCLC brain metastases. 21 and 22 are also part of a very limited set of kinase inhibitors reportedly specifically designed for the treatment of brain cancer.
PI3K/AKT/mTOR
ARTICLE SECTIONS
In addition to targeting EGFR directly, another approach to treat GBM would be to target downstream kinases. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) kinases comprise one such pathway and are implicated in a significant percentage of GBM and neuroblastoma cases.(80-83) Targeting the PI3K/AKT/mTOR pathway is also suggested as a mechanism to treat human epidermal growth factor receptor 2 (HER2)-positive brain metastases.(84) As a result of this biological implication and the pursuit of inhibitors of this pathway for other tumors, a number of agents have advanced to clinical trials in GBM patients.(85) As the inhibitors of the PI3K/AKT/mTOR pathway have been reviewed in this context previously,(85) we provide here a brief summary organized according to primary target of the inhibitor.
Of the many PI3K/mTOR inhibitors that have entered clinical study, GDC-0084 (25),(86) buparlisib (26),(87) PX-866 (28),(88) pilaralisib (29),(89) and XL765 (30)(90) have been part of trials specifically for GBM (Table 4).(83) Buparlisib has also advanced to clinical studies for the treatment of breast cancer patients with brain metastases.(91) However, among these, only 25 was apparently designed to ensure significant free brain penetration.
Table 4. Structures and Key Properties for PI3K Inhibitors Advanced to Clinical Study for Brain Cancer or FDA Approveda
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
In order to realize 25, a program was initiated to purposefully identify a PI3K/mTOR inhibitor capable of crossing the BBB so that it would be amenable to treating GBM. These studies began with GNE-493 (23)(92) as a starting point which was a potent inhibitor of PI3K and mTOR but was a substrate of P-gp and Bcrp (Figure 2).(86) In order to realize brain penetrant analogs, the importance of reducing the number of hydrogen bond donors in 23 was identified as critical. To further predict the likelihood of P-gp and Bcrp mediated efflux, as well as metabolic stability, in silico evaluations were used to prospectively evaluate designs. From these efforts GNE-317 (24, Figure 2) was first identified which demonstrated that a brain penentrant PI3K inhibitor differentiated from a PI3K inhibitor that does not penetrate the BBB (2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno[3,2-d]pyrimidine (GDC-0941),(93) not shown) in that it had a PD effect in normal brain tissue and had improved efficacy in in vivo brain tumor models.(94)24 was found to have unacceptable projected human clearance and so was further optimized to 25 (Figure 2), a molecule that is of comparable potency and has similar ability to cross the BBB to 24 but was projected to have more desirable human pharmacokinetic properties. The ability of 25 to potently inhibit PI3K/mTOR signaling in the brain, along with its desirable projected human pharmacokinetic profile, led to its advancement to clinical trials for the treatment of GBM.
Figure 2
Figure 2. Modifications of PI3K/mTOR inhibitors that resulted in the discovery of 25, a brain penetrating inhibitor with desirable metabolic stability.
The report of the discovery of buparlisib (26) does not indicate that achieving brain penetration was a design consideration.(87) However, in subsequent reports buparlisib has been reported to effectively cross the BBB and inhibit PI3K pathway signaling in preclinical(95) and early clinical studies in patients with recurrent GBM.(96) Unfortunately and despite inhibition of PI3K signaling in patient tumors, there was not substantial efficacy. Additionally, buparlisib has been reported to cause mood changes, a side effect not observed with other PI3K inhibitors in the clinical setting.(84) The structurally related dual PI3K/mTOR inhibitor PQR309 (27) is reported to not be a substrate of P-gp(97) and achieves equivalent brain and plasma concentrations,(98) although free concentrations were not reported.
The inhibitors 28, pilaralisib (29), and 30 have each progressed to clinical trials for the treatment of GBM, but there has not been a report of whether brain penetration was a design consideration or if these molecules penetrate the BBB.
The PI3K and PI3K/mTOR inhibitors discussed above inhibit each of the class I PI3K isoforms (α, β, δ, and γ). However, the only as yet approved PI3K inhibitor is idelalisib (31), a selective inhibitor of the δ isoform of PI3K.(99) Idelalisib is approved for the treatment of chronic lymphocytic leukemia. We were unable to identify any indications that CNS tumor progression is a mechanism of resistance to idelalisib. This is a potential risk, as idelalisib is reported to not penetrate the BBB,(100) consistent with the disclosure that it is a substrate of both P-gp and Bcrp.(101)
Among mTOR inhibitors, the mTORC1 inhibitors everolimus (32), temsirolimus (33), and sirolimus (34) are FDA approved agents (Table 5).(102) Each of these molecules has been studied in patients with GBM but has not provided benefit.(83) Perhaps insufficient brain penetration is a contributing factor to the lack of efficacy, as everolimus and sirolimus are reported to be substrates of P-gp (and temsirolimus is a prodrug of sirolimus).(103)
Table 5. Structures and Key Properties for mTOR Inhibitors Advanced to Clinical Study for Brain Cancera
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
AZD2014 (35)(104) and CC-223 (36)(105) are mTORC1/2 inhibitors that have advanced to GBM clinical trials.(106, 107) For 35, there is no indication of whether the molecule penetrates the BBB.(108) In a clinical study of 36, GBM tumor-to-plasma ratios ranged from 16% to 77%.(107) However, it is not possible to ascertain if sufficient concentrations to expect efficacy are achieved as free concentrations were not reported, including where the BBB is intact.
Most encouraging of the clinical mTOR inhibitors from the perspective of trying to treat brain cancer, palomid 529 (37) has been reported to effectively cross the BBB as brain concentrations were similar in pharmacokinetic experiments comparing wild type mice and P-gp knockout mice.(109) This makes 37 one of a small set of clinical kinase inhibitors (the only apparent mTOR inhibitor) where limited brain penetration would not be a principal factor in limiting conclusion on the value of a target.
In addition to the inhibition of PI3K and mTOR, inhibition of AKT has received significant attention in this pathway.(110) Among the clinical AKT inhibitors perifosine (38),(111) 8-(4-(1-aminocyclobutyl)phenyl)-9-phenyl[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one (MK-2206, 125),(112) PBI-05204 (39),(113) 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693),(114) uprosertib,(115) XL-418 (structure not disclosed), (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (GDC-0068),(116) and 3-(3-(4-(1-aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ-092),(117) we were only able to identify some indication of the likelihood of brain penetration, or advancement to a clinical study for use in brain cancer, for perifosine and 39 (Table 6). Ultimately, the allosteric AKT inhibitor perifosine was part of a trial in GBM patients but did not demonstrate efficacy,(83) consistent with limited (total) brain penetration preclinically.(118) In a preclinical study of 39, significant total brain concentrations were achieved in rats but no assessment of free concentration was determined.(119) Additionally, for 125, a trial of GBM patients was deemed not suitable due to “questions regarding the ability of the drug to pass through the blood–brain barrier”.(83)
Table 6. Structures and Key Properties for Select AKT Inhibitors Advanced to Clinical Studya
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
Achieving brain penetration was not an apparent design consideration for any clinical AKT inhibitor, and no clinical AKT inhibitor is conclusively capable of achieving signficant free brain concentrations, suggesting opportunity remains for AKT inhibitors that might be used to treat brain cancers.
FGFR
ARTICLE SECTIONS
Fibroblast growth factor receptor (FGFR) kinase has been suggested as a potential target for the treatment of brain cancer,(120, 121) and numerous FGFR inhibitors have entered clinical development.(122) As many of the FGFR inhibitors are nonselective, with many inhibiting VEGFR and PDGFR (discussed above), the focus of this section is limited to selective FGFR inhibitors that have entered clinical development (Table 7).(123) Those inhibitors include AZD4547 (40),(124) infigratinib (41),(125) erdafitinib (42),(126) CH5183284 (43),(127) and ARQ 087 (structure not available). Of these, infigratinib has advanced to clinical studies in patients with GBM.(128) However, we were unable to identify any data that suggest infigratinib is capable of penetrating the BBB. Similarly, we were unable to identify data informing the potential of erdafitinib, 40, or 43 to freely cross the BBB. On the other hand and of interest for its potential for the treatment of brain cancer, ARQ 087 was reported to achieve free brain-to-free plasma concentration ratios of about 0.1 in rats.(129)
Table 7. Structures and Key Properties for FGFR Inhibitors Advanced to Clinical Studya
| compd | primary kinase target | HBD | TPSA (A2) | cLogP | MW | preclinical assessment of brain penetration |
|---|---|---|---|---|---|---|
| 40 | FGFR | 3 | 91 | 4.4 | 464 | no data reported |
| 41 | FGFR | 2 | 95 | 4.7 | 560 | no data reported |
| 42 | FGFR | 1 | 77 | 4.3 | 447 | no data reported |
| 43 | FGFR | 4 | 105 | 3.4 | 356 | no data reported |
| CNS drugs* | N/A | 1 | 45 | 2.8 | 305 |
a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
IGF-1R
ARTICLE SECTIONS
Type I insulin growth factor receptor (IGF-1R) has been identified as a potential target for the treatment of brain cancers,(120, 130) and numerous IGF-1R inhibitors have advanced to clinical trials.(131) Among the clinical IGF-1R inhibitors (Table 8) linsitinib (44),(132) BMS-754807 (45),(133) BVP-51004 (46),(134) XL-228 (47),(135) and INSM-18 (48),(136) there is no indication that achieving CNS penetration was a design consideration. 45 was demonstrated to have limited total brain penetration in mouse studies,(137) and 48 is believed to be a substrate of P-gp.(138) We were unable to identify data related to efflux transport or brain penetration of the other IGF-1R inhibitors. Unfortunately, the available data suggest that no clinical IGF-1R inhibitors are suitable to evaluate whether inhibition of this target would be beneficial for brain cancer treatment.
CDKs
ARTICLE SECTIONS
In addition to aberrant EGFR and PI3K signaling pathways, activation of cyclin-dependent kinases (CDK) 4 and 6 is observed in a majority of GBM cases.(82, 139) Furthermore, CDK4/6 amplification is frequently observed in diffuse intrinsic pontine gliomas, a cancer of the brainstem.(140) Among CDK4/6 inhibitors, palbociclib (49, Table 9)(141) is approved for the treatment of hormone-receptor positive breast cancer. Regarding its potential for the treatment of brain cancer, palbociclib was demonstrated to provide a survival benefit in a genetic mouse model of brainstem glioma.(142) Preclinical studies in three intracranial mouse models of GBM showed that palbociclib was efficacious either as a single agent or in combination with radiation.(143) However, palbociclib was found at 25-fold higher concentration in tumor than in normal brain tissue, suggesting that the molecule has limited penetration into the brain and the BBB is compromised at the core of the tumor but not in normal brain tissue. Therefore, despite the reports of efficacy in brain cancer models, palbociclib may have free brain concentrations below what is needed for efficacy in tumors where the BBB is intact. This would be consistent with being a substrate of P-gp,(144) and ultimately an assessment of free brain concentrations or Kpuu,brain is necessary to draw a conclusion about the merits of palbociclib for use in brain cancer.
Table 9. Structures and Key Properties for CDK4/6 Inhibitors Advanced to Clinical Studya
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
Like palbociclib, abemaciclib (50)(145) is reported to be a substrate of both P-gp and Bcrp.(146) However, in mice and rats, Kpuu,brain is measurable at at least 0.2 and, while perhaps a model of modest utility, abemaciclib demonstrated efficacy in an orthotopic U87 GBM model in rats.(146, 147) While there is potential to further increase free brain penetration, given that some free brain exposure is attained with abemaciclib, it is encouraging that a trial studying abemaciciblib in breast cancer, non-small-cell lung cancer, or melanoma patients with brain metastases is currently enrolling.(148) To the best of our knowledge, there is no evidence of brain penetration for other CDK4/6 inhibitors, including the clinical inhibitor ribociclib (51).(149)
In addition to the potential of CDK4/6 inhibition in the treatment of brain cancer, inhibition of CDK1 and CDK2 has been suggested as having potential application in the treatment of GBM.(150) The CDK inhibitors that have advanced to the clinic that inhibit CDK1/2 tend to be broad spectrum CDK inhibitors (Table 10).(149)
Table 10. Structures and Key Properties for CDK1/2 Inhibitors Advanced to Clinical Studya
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
Flavopiridol (52, Table 10)(151) has been shown to inhibit GBM tumor models in mice, including in the intracranial setting.(152) However, the value of the in vivo efficacy may be limited by a compromised BBB, as flavopiridol is a substrate of both P-gp and Bcrp and significantly increased brain exposure is observed in P-gp/Bcrp knockout mice than in wild type mice.(153)
Seliciclib (53, Table 10) was reported to achieve a brain-to-plasma ratio (AUC) of 0.3 after a 25 mg/kg oral dose to rats.(154) However, this only considers the total concentrations, and the free concentration ratio is likely to be lower as seliciclib is a reported substrate of P-gp.(155)
Dinaciclib (54, Table 10)(156) has demonstrated potential utility in in vitro studies to treat GBM;(157) however, we were unable to identify any data suggesting whether or not this molecule is likely to penetrate the BBB.
Despite inhibition of neuroblastoma tumor cell growth in the in vitro setting,(158) SNS-032 (55, Table 10) is a substrate of P-gp and brain penetration is limited in wild type mice compared to P-gp knockout mice.(159)
AT7519 (56, Table 10)(160) appears to be a substrate of P-gp as it has less of an effect on P-gp overexpressing cell lines.(161) We were not able to determine if R547 (57)(162) and AZD5438 (58)(163) are capable of crossing the BBB or are substrates of efflux transporters. Furthermore, we were unable to identify any indication that achieving CNS penetration was a design consideration in the discovery of any of the inhibitors of the CDKs 1 and 2. Taken together, there remains an apparent lack of a CNS penetrating CDK1/2 inhibitor if clinical assessment of this target for the treatment of GBM is to be assessed.
ALK
ARTICLE SECTIONS
Outside primary brain tumors, there is a growing recognition of the ability of peripheral tumors to escape therapy via metastasis to the brain. As a result, there are emerging best-in-class opportunities for kinase inhibitors that prevent resistance in that manner. An example of this phenomenon is seen in the case of anaplastic lymphoma kinase (ALK) fusion positive NSCLC.(164) Crizotinib (59)(165) was the first ALK inhibitor to show remarkable benefit to ALK-positive NSCLC patients.(166) Unfortunately, disease progression on crizotinib therapy is inevitable. In fact, in the phase I and II trials of crizotinib in ALK-positive NSCLC, the most common mechanism of progression on therapy has been reported to be through CNS metastases.(167, 166) Crizotinib has poor free brain penetration, consistent with significant P-gp mediated efflux in vitro, which likely allows for metastases to find “sanctuary” in the CNS allowing for disease progression.(168, 169) As a result of relapse through CNS metastases, as well as resistance mechanisms including kinase domain mutations, there has been a substantial effort in identifying next-generation ALK inhibitors, which have been reviewed elsewhere.(170)
Among the many next-generation inhibitors (Table 11), several have been reported to be potentially effective in controlling CNS disease in ALK-positive NSCLC. In a small set of patients in a phase I trial, ceritinib (60)(171) was reported to achieve responses in patients with brain metastases, including patients who had progressed on crizotinib.(172) For ceritinib, medicinal chemistry optimization did not apparently focus on achieving free brain exposure.(171)
Table 11. Structures and Key Properties for ALK Inhibitors Advanced to Clinical Studya
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
While, to the best of our knowledge, P-gp transport or free brain penetration was not apparently a factor in the design of the molecule, alectinib (61)(173) is reported to be efficacious in preclinical models of brain metastases and, aiding in the positive interpretation of the efficacy results, alectinib is reportedly not a substrate of P-gp.(174) Most significantly, alectinib has been reported to achieve responses in patients with CNS disease that did not respond to crizotinib, indicating some degree of brain penetration.(175)
Entrectinib (62)(176) is reportedly capable of crossing the BBB in preclinical species, although free brain concentrations were not reported. Encouragingly, a clinical report of a NSCLC patient with brain metastases who had a response to entrectinib suggests that the molecule may achieve significant free CNS penetration.(177)
ASP3026 (63)(178) was reported to achieve a brain-to-plasma ratio (AUC0–24h) of 0.72 in mice.(179) Free brain-to-plasma ratios were not reported, however. Brigatinib (64)(180) is another next-generation ALK inhibitor that has some preliminary indication of efficacy in a cohort of 10 crizotinib resistant patients with brain metastases.(181) Brigatinib was able to achieve a response in a mouse intracranial tumor model, and 11C brigatinib was visualized within the tumor. However, in these studies, the extent to which the BBB was compromised was not reported and higher concentrations of brigatinib were observed in the intracranial tumor than in normal brain tissue.(181) While insufficient preclinical data exist to understand the extent to which free brigatinib is capable of penetrating the BBB, very encouraging clinical data are emerging showing that brigatinib is effective in treating ALK-positive brain metastases, where crizotinib was ineffective, suggesting meaningful CNS penetration of brigatinib in these patients.(182)
X-376 (65)(183) and X-396 (structure not disclosed, 126) are additional ALK inhibitors. 126 is reported to have a brain-to-plasma ratio in mice comparable to that of crizotinib (a P-gp substrate with low CNS exposure in humans). However, the investigators suggest that due to the greater potency of 126, there may be potential for efficacy in the CNS setting.(183) No reports of free brain levels are reported, however.
While each of the aforementioned next-generation ALK inhibitors (Table 10) may hold potential for treating ALK-positive malignancy, there is insufficient preclinical data to demonstrate that these molecules lack transporter mediated efflux and/or achieve significant free brain exposure.
PF-06463922 (66, Table 11)(169) clearly stands out among the next generation ALK inhibitors, as achieving free brain penetration was an evident design consideration. 66, which has activity against both EML4-ALK fusion proteins and crizotinib resistant ALK mutants, was designed to be a brain penetrant ALK inhibitor by reducing P-gp transport.(169)
As resistance to crizotinib is acquired through various kinase mutations as well as CNS metastases, the Pfizer program sought to achieve a molecule that would simultaneously overcome both of those resistance mechanisms.(169) Initial analogs capable of potently inhibiting crizotinib resistant ALK mutations did not achieve a desirable balance of potency with physicochemical properties that allowed for both good metabolic stability and low P-gp mediated efflux. Crystallographic information was utilized to design subsequent ALK inhibitors with improved lipophilic efficiency. The “U-shape” that ligands adopted in a cocrystal structure with ALK inspired macrocyclic analogs. A 12-membered ring lactam was found to improve human liver microsomal stability and reduce P-gp efflux when compared to its acyclic counterpart (66 vs 67, Figure 3). Rather than focusing on the influence of single physicochemical properties on P-gp mediated efflux, the Pfizer group emphasizes the need for multiparameter optimization due to an interplay of the influence of numerous physicochemical properties on efflux. In particular, HBD, log D, and MW were each considered in parallel. In these studies, acyclic analogs had higher levels of P-gp mediated efflux than the macrocycles with comparable MW, log D, and HBD. 66, like the other macrocycles as well as acyclic analogs described, takes advantage of an intramolecular hydrogen bond between the aminopyridine and the adjacent ether oxygen. This intramolecular hydrogen bond may effectively mask a HBD. The authors also suggest that the macrocycles may have reduced efflux relative to acyclic analogs due to a reduced number of rotatable bonds and a 10% smaller solvent-accessible surface area.(169) Ultimately, 66 achieves a free brain-to-free plasma AUC ratio of 0.2 after oral administration in rats.
Figure 3
Figure 3. Macrocyclization led to improved metabolic stability, potency, and reduced P-gp mediated efflux in this series of ALK inhibitors.
In summary, ALK is one of a few kinase targets, along with PI3K, EGFR, and PLK (below), where discovery programs have been reportedly directed specifically at achieving brain penetrating inhibitors. With such an ALK inhibitor undergoing clinical study currently, evaluation of the clinical hypothesis can take place.
HER2
ARTICLE SECTIONS
A parallel to the resistance to initial ALK inhibitors via brain metastasis is observed in the treatment of HER2-positive breast cancer with antibody therapeutics. Among patients treated with trastuzamab (Herceptin), CNS metastases emerge in approximately 30% of patients.(184) Lapatinib (68, Table 12) is approved as a small molecule HER2/EGFR inhibitor,(185) but preclinical studies showed that therapeutic concentrations were not achieved in brain metastases,(186) suggesting that lapatinib does not effectively cross the BBB and would not be expected to be efficacious in that setting. Furthermore, a study of brain-to-plasma concentration ratios in mice shows that lapatinib is a substrate of P-gp and Bcrp.(187) Indeed, in the clinical setting lapatinib was found to have variable and limited penetration into HER2-positive brain metastases.(188, 91) Aside from lapatinib, at least a dozen additional small molecule inhibitors of HER2 have been reported to have advanced to clinical study (Table 12).(189)
Table 12. Structures and Key Properties for HER2 Inhibitors Advanced to Clinical Studya
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
Among the HER2 inhibitors that have advanced to clinical studies, neratinib (69),(190) a pan-HER inhibitor, and tucatinib (70)(191) have advanced to trials for breast cancer patients with brain metastases. Unfortunately, a phase II trial of neratinib in patients with HER2-positive brain metastases was not successful. The lack of efficacy attained in the trial may be due in part to the noted lack of CNS penetration of neratinib, determined in preclinical studies(192) and consistent with a report that it is a P-gp substrate.(193) For tucatinib, on the other hand, an active metabolite is reported to achieve brain-to-plasma concentration ratios ranging from 0.5 to 2.1 across several time points after a 75 mg/kg oral dose in mice.(194) While only total concentration ratios were reported, and so a true indication of free brain penetration is not available, in other studies tucatinib was capable of inhibiting p-HER2 in mouse brain tissue, demonstrating some extent of free exposure. Additionally, tucatinib achieved a survival benefit in mice in an intracranial HER2-positive xenograft study.(191)
TAK-285 (71)(195) is a clinical inhibitor of HER2 and EGFR that has been demonstrated to be capable of penetrating the BBB in preclinical studies. In rats, the free brain-to-free plasma (AUC) ratio was 0.24 after a 75 mg/kg oral dose.(196) Additionally, 71 was demonstrated to not be a substrate of P-gp and to confer efficacy in a mouse model of HER2-positive brain metastases.(197) Taken together, the data are supportive of evaluating 71 in the clinical treatment of patients HER2-positive brain metastases.
Dacomitinib (72)(198) inhibits epidermal growth factor receptors and other tyrosine kinases. A clinical study is looking at the safety and effectiveness of using dacomitinib to treat HER2-positive breast cancer patients with progressive brain metastases (NCT02047747). Unfortunately, there are apparently no data available on whether dacomitinib is a substrate of efflux transporters that are expressed at the BBB.
The pan-HER inhibitor AC480 (73)(199) was utilized in a study of patients with GBM in which the tumor was surgically resected after drug administration. This study showed that 73 had concentrations in the tumor and brain that were greater than in plasma, although no indication of free concentrations has been reported that would help to interpret whether efficacy could have been expected.(200)
The HER2/EGFR/VEGFR inhibitor AEE788 (74)(201) was of interest for the treatment of brain cancers. In preclinical studies, 74 had activity against medulloblastoma cell lines and a xenograft (flank).(202) While 74 was reported to confer a survival benefit in an orthotopic model of glioblastoma in mice, we were not able to identify reports of whether 74 is an efflux transporter substrate or if it is capable of free brain penetration.(203) Unfortunately, a phase I trial of 74 enrolling GBM patients needed to be discontinued due to toxicity of the molecule without benefit.(204)
Pelitinib (75)(205) is another HER2/EGFR inhibitor that has advanced to clinical studies but is reported to be a substrate of Bcrp which might limit its CNS exposure.(206) The HER2 inhibitor CP-724,714 (76)(207) was reported to be a substrate of both P-gp and Bcrp and, accordingly, would not be expected to be able to effectively cross the BBB.(208)
CUDC-101 (77),(209) sapitinib (78),(210) and AST1306 (79)(211) have advanced to clinical trials, but we were unable to identify whether or not these molecules are substrates of efflux transporters or whether they are capable of free penetration of the BBB.
The data available for tucatinib and 71 demonstrate that brain penetrant inhibitors of HER2, which would be of evident interest in the treatment of HER2-positive brain metastases, are achievable, and it is encouraging that a potential treatment for HER2-positive brain metastases may be realized.
b-Raf/MEK
ARTICLE SECTIONS
Historically, melanoma patients have a high frequency (>90%) of brain metastasis development, and once present, these patients typically survive for less than 6 months.(212) Recently, inhibitors of the V600E mutation of b-Raf (vemurafenib (80)(213) and dabrafenib (81)(214)) and mitogen activated protein kinase (MEK) inhibitors (cobimetinib (85)(215) and trametinib (86)(216)), along with the combination of dabrafenib and trametinib, have received approval for the treatment of melanoma. As b-Raf (including V600E mutant) and MEK inhibitors are used in the treatment of melanoma, it is important to consider how effectively these agents cross the BBB to either treat or prevent CNS metastases.(217) Additionally, b-Raf(218) and MEK(219) have been identified as potential targets for primary brain tumors. At least seven Raf inhibitors(220) and more than a dozen MEK inhibitors(221) have entered clinical studies.
Among the clinical Raf inhibitors (Table 13), there have been conflicting reports of clinical response of CNS metastases to vemurafenib (80)(222) or dabrafenib (81)(223) therapy, ranging from ineffective at treating brain metastases to a case of a complete response. Both vemurafenib and dabrafenib have been reported to be substrates of P-gp and Brcp and, furthermore, achieve little free brain penetration in mouse studies.(224, 225) The varied reports and modest clinical response rates could be attributed to inconsistent disruption of the BBB, and potentially greater rates of response could be achieved if a b-Raf inhibitor were capable of free brain penetration.
Table 13. Structures and Key Properties for b-Raf Inhibitors Advanced to Clinical Studya
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
Raf-265 (82)(226) does not apparently effectively cross the BBB, as that molecule conferred efficacy in a mouse tumor model when implanted in a flank but not when implanted intracranially.(227) We were unable to identify any information suggesting whether or not the clinical Raf inhibitors encorafenib (83),(228) XL281 (structure not disclosed), RO5212054 (structure not disclosed), ARQ-736 (84),(229) or its active metabolite, are capable of penetrating the BBB or are efflux transporter substrates. Together, the available data suggest that a BBB penetrating Raf inhibitor remains elusive, yet there would be significant potential value for such an inhibitor in treating cancers that metastasize to the brain.
The approved MEK inhibitors cobimetinib (85, Table 14) and trametinib (86, Table 14) have each also been reported to have limited free brain penetration in mice due to P-gp and Bcrp mediated efflux.(230, 224) Additionally, neither cobimetinib nor trametinib inhibited pERK in normal brain tissue in mice after oral administration despite inhibition in the periphery, further illustrating a lack of CNS penetration by these molecules.(231) Furthermore, when coadministered, dabrafenib and trametinib had low mouse brain exposure as well.(224)
Table 14. Structures and Key Properties for MEK Inhibitors Advanced to Clinical Studya
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
Among the other clinical MEK inhibitors,(221) we were unable to identify any data that would suggest that GDC-0623 (87), binimetinib (88), selumetinib (89), CI-1040 (90), TAK-733 (91), RO5126766 (92), or WX-554 (structure not disclosed) would be likely to penetrate the BBB. Nevertheless, selumatinib and binimetinib have been studied clinically for the treatment of brain cancers.(232, 233)
The MEK inhibitor PD0325901 (93)(221) inhibited tumor growth in a LN229 intracranial glioblastoma mouse xenograft tumor model study.(219) Additionally, that 93 is capable of penetrating the BBB in rats was demonstrated by significant inhibition of pERK in normal brain tissue after oral administration of the drug. This molecule was found to have neurologic toxicities clinically, and with the hope to avoid similar toxicities, refametinib (94) and RO4987655 (95) were reportedly designed specifically to not penetrate the BBB.(234, 235) Accordingly, despite substantial peripheral exposure in rat or mouse studies, inhibition of pERK in brain tissue by those molecules was negligible. Likewise, AZD8330 (96)(221) is reported to achieve minimal CNS penetration in rats.(236)
Pimasertib (97)(221) has been reported to inhibit pERK in mouse brain tissue, indicating some degree of CNS penetration.(237) Consistent with those results, pimasertib was reported to not be a substrate of efflux transporters.(238)
E6201 (98),(239) an inhibitor of MEK and other kinases, has been shown to achieve total brain-to-plasma concentration ratios of 4.8–6.4 in rodents, although free concentrations were not reported. To support the suggestion that some 98 is free to engage its target in mouse brains, the molecule demonstrated a survival benefit in a mouse model of brain metastases.(240)
While in no case was achieving free brain penetration of a MEK inhibitor a reported design consideration, two clinical MEK inhibitors discussed above have achieved significant CNS concentration in preclinical studies. Worth noting, those two MEK inhibitors (93 and 97) each have a dihydroxy hydroxamate moiety (the only two among those in Table 14) and have four nominal hydrogen bond donors. It is therefore curious that the physical properties of 93 and 97 are so inconsistent with the median values of marketed CNS drugs in the HBD category, which is known to have a substantial impact on P-gp efflux. However, both 93 and 97 have the potential for multiple intramolecular hydogen bonding interactions which could reduce both the effective HBD count and polarity of these molecules. While the brain penetrant MEK inhibitors offer opportunity to study their benefit in patients with brain cancer, 93 also highlights the additional risk that brain penetration of small molecule drugs adds to to an already difficult development path. Both on- and off-target activities in the brain have the potential to render a drug less tolerated, potentially limiting the ability of such a molecule to benefit patients with peripheral malignancy.
PLK1/Aurora Kinases
ARTICLE SECTIONS
Both Polo-like kinase (PLK)(241) and Aurora kinases have been suggested as targets for the treatment of brain cancers.(242, 243) Among the PLK1 inhibitors that have advanced to the clinic (Table 15), volasertib (99),(244) BI 2536 (100),(245) GSK 461364 (101),(246) rigosertib (102),(247) and NMS-P937 (103)(248) have been shown to be substrates of P-gp, and therefore, CNS penetration is expected to be limited.
Table 15. Structures and Key Properties for PLK Inhibitors Advanced to Clinical Studya
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
The PLK1 inhibitor TAK-960 (104, Table 15), however, was reportedly selected among other analogs because it had reduced P-gp mediated efflux, suggesting the potential for CNS penetration.(249) In the discovery of 104, it was noted that incorporation of a substituent capable of acting as a hydrogen bond acceptor adjacent to an amide, effectively eliminating a hydrodgen bond donor via intramolecular hydrogen bond, was essential to reduce P-gp mediated efflux (Figure 4).
Figure 4
Figure 4. Reducing effective HBD count by intramolecular hydrogen bonding reduced P-gp efflux among a set of PLK1 inhibitors.
At least 15 Aurora kinase inhibitors have advanced to clinical studies.(250) We were unable to identify considerations of achieving CNS exposure in the discovery of those molecules. Among those Aurora kinase inhibitors that have entered clinical studies, any discussion of potential BBB penetration is limited to tozasertib (105)(250) and alisertib (106)(250) (Table 16) which were each reported to inhibit tumor growth in orthotopic GBM models in mice, which is insufficient to understand the extent to which those molecules are capable of freely penetrating the BBB.(243, 251)
Table 16. Structures and Key Properties for Clinical Aurora Inhibitors for Which BBB Penetration Data Are Availablea
| compd | primary kinase target | HBD | TPSA (A2) | cLogP | MW | preclinical assessment of brain penetration |
|---|---|---|---|---|---|---|
| 105 | pan-Aurora | 3 | 102 | 4.8 | 465 | insufficient data |
| 106 | Aurora A | 2 | 105 | 6.2 | 519 | insufficient data |
| CNS drugs* | N/A | 1 | 45 | 2.8 | 305 |
a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
PKC
ARTICLE SECTIONS
Protein kinase C (PKC) has been identified as a potential target for the treatment of GBM.(252) Among the small molecule PKC inhibitors that have entered clinical studies for the treatment of cancer (Table 17) are bryostatin (107), enzastaurin (108), midostaurin (109), and UCN-01 (110).(253) Among these, enzastaurin was part of a trial for the treatment of GBM,(254) as well as for the treatment of brain metastases from lung cancer,(255) but in each case it did not demonstrate significant benefit. Along with enzastaurin, we were unable to identify any data suggesting whether or not bryostatin or midostaurin is capable of penetrating the BBB or is a substrate of efflux transporters P-gp or Bcrp.
Table 17. Structures and Key Properties for PKC Inhibitors Advanced to Clinical Studya
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
The PKC inhibitor 110 achieved total brain-to-plasma concentration ratios of 0.5–1.0 at five different time points after a 3.5 mg/kg dose to rats.(256) However, free concentrations are not reported, and so a proper interpretation of free brain penetration is not available from this study. Additionally, 110 is a reported substrate of P-gp, anticipated to limit CNS penetration.(257)
ABL and Src
ARTICLE SECTIONS
The discovery of imatinib (111, Table 18)(258) has rightfully been heralded as a remarkable success story in targeted therapeutics for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL). Despite initial responses, however, in addition to the emergence of resistance mutations,(259) brain metastases lead to progression on imatinib therapy in nearly 20% of patients.(260) Such CNS resistance likely emerges due to the poor ability of imatinib to cross the BBB, demonstrated both preclinically and clinically, as it is a P-gp and Bcrp substrate.(261)
Table 18. Structures and Key Properties for Abl or Src Inhibitors Advanced to Clinical Studya
Table a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
Dasatinib (112, Table 18) was discovered as a next-generation Bcr-Abl inhibitor that potently inhibits imatinib resistant mutant forms of the enzyme.(262) Dasatinib also inhibits Src, among other kinases,(263) which has been identified as a potential target for the treatment of GBM as well as a target for patients with brain metastases.(264) Like imatinib, dasatinib is a substrate of both P-gp and Bcrp which limits its brain penetration.(265) Yet, despite approximately 10% (total) brain penetration (relative to plama) in an intracranial mouse model of Ph+ CML, dasatinib was able to demonstrate a therapeutic benefit. The authors attribute the efficacy to the exceptional potency of dasatinib against the relevant enzymes driving tumor growth.(266) In a small clinical study, all of the 11 evaluable patients with CNS chronic myeloid leukemia responded to dasatinib therapy. Also, of 22 patients from whom CSF samples were obtained, dasatinib was detectable in 6 of those patients, with CSF-to-plasma (total) of 0.05–0.28.(266) These encouraging results suggest that a CNS penetrant Bcr-Abl inhibitor has potential for significant clinical benefit.
Adding to data suggesting the benefit of CNS penetrant Bcr-Abl inhibitors, bosutinib (113) is another inhibitor of Bcr-Abl and Src family kinases, along with other kinases.(263) In rats, bosutinib has been reported to achieve brain-to-plasma ratios ranging from 2.0 to 0.4; however there was not an accounting for free concentrations, so interpretation is limited. Yet bosutinib is reported to not be a significant substrate of P-gp or Bcrp.(267) While there has been a report of a patient with ALL, which includes the CNS, who achieved a response to bosutinb,(268) a phase II clinical trial of bosutinib in patients with GBM was halted early due to lack of benefit.(269)
Nilotinib (114) has been reported to be a substrate of P-gp,(270) and achieving CNS penetration was not a reported consideration in its discovery.(271) Despite this, in a small clinical study of four patients with CNS progression of CML, nilotinib was able to achieve a median CSF-to-plasma (total) ratio of 0.53%. With plasma protein binding reported to be 98% for nilotinib, this would translate to an approximately 26% CSF-to-free plasma ratio.(272) Along with the apparent CNS penetration, 3 of the 4 patients had a clinical response to nilotinib.(272) Further suggestive of some CNS penetration of both nilotinib and bosutinib are reports describing the use of these molecules in preclinical models of neurodegeneration in which pharmacodynamic modulation changes are observed in rodent brains.(273)
In the initial report describing the discovery of the Bcr-Abl inhibitor ponatinib (115), brain penetration was not reported as a design consideration.(274) Still, the authors suggest that ponatinib is capable of crossing the BBB, as in a mouse study, a brain/plasma concentration ratio of 1.6 was achieved. As total (as opposed to free) concentrations were used to calculate the ratio, little conclusion can be drawn about how effectively ponatinib is capable of crossing the BBB based on that data. Suggesting that the action of P-gp and Bcrp actually does limit penetration of ponatinib across the BBB is a study comparing brain and plasma exposure in both wild type and P-gp/Bcrp knockout mice. In this study, the AUCbrain in the transporter knockout mice was 18-fold higher than in wild type mice.(275)
Bafetinib (116)(276) is a Bcr-Abl/Lyn inhibitor that has advanced to clinical study for the treatment of brain cancers. Unfortunately, in a clinical study monitoring brain concentrations by microdialysis, bafetinib was demonstrated to not effectively cross the BBB.(277) Consistent with the clinical findings, preclinical studies demonstrated that efficacy in a preclinical CNS cancer model was significantly improved with coadministration of a P-gp inhibitor, implying bafetinib is a significant substrate of that transporter.(278)
While achieving CNS penetration is not discussed as a design consideration in the discovery of saracatinib (117),(279) in preclinical studies it was reported to achieve brain-to-plasma concentration ratios of about 0.5 and CSF-to-plasma ratios of about 0.2.(280) The brain and plasma concentrations reported were total (as opposed to free), and so there is a limit to the interpretation of brain penetration of this agent. However, in a clinical study evaluating saracatinib in Alzheimer’s patients, CSF-to-free plasma ratios were about 0.3, indicating some ability of this molecule to freely reach the CNS.(281)
c-Met
ARTICLE SECTIONS
Inhibition of c-Met has been suggested as a possible approach to treat brain cancer.(282) The clinical c-Met inhibitor foretinib (118)(283) has been reported to achieve brain-to-plasma ratios approaching 0.2 in mice; however, only total concentrations were reported.(284) SGX523 (119),(285) a c-Met inhibitor, was reported to confer efficacy in an orthotopic U87 xenograft model.(286) However, no indication of the extent of brain penetration of the molecule or whether it is a substrate of efflux transporters is available, and so a conclusion on the expected potential utility of this molecule for the treatment of CNS malignancy cannot be drawn. Although numerous other nominal c-Met inhibitors have entered clinical trials,(287) we were unable to identify any indication that these molecules(288) achieve brain penetration (Table 19).
Table 19. Structures and Key Properties for Clinical c-Met Inhibitors for Which Discussion of Brain Penetration Was Found in the Literaturea
| compd | primary kinase target(s) | HBD | TPSA (A2) | cLogP | MW | preclinical assessment of brain penetration |
|---|---|---|---|---|---|---|
| 118 | MET, RON, Axl, VEGFR | 2 | 111 | 4.2 | 633 | insufficient data |
| 119 | MET | 0 | 73 | 2.6 | 359 | insufficient data |
| CNS drugs* | N/A | 1 | 45 | 2.8 | 305 |
a
Properties for 119 marketed CNS drugs are included for comparison. *Median value of 119 marketed CNS drugs.(12)
FAK/Pyk2
ARTICLE SECTIONS
Focal-adhesion kinase (FAK) and proline rich tyrosine kinase 2 (Pyk2) have been implicated as potential targets for the treatment of brain cancers.(289) Additionally, four FAK or FAK/Pyk2 inhibitors have advanced to clinical study (Table 20).(290) For PF-562,271 (120),(291) defactinib (121),(292) and PND-1186 (122)(293) we were unable to to identify any reported characteristics that would indicate whether the molecule is capable of penetrating the BBB. GSK-2256098 (123)(294) is reported to have “poor” penetration of the BBB in rodent PK studies. By PET, in human GBM patients, significant brain and tumor concentrations relative to blood are reported but nonspecific binding was not apparently factored.(295) Taken together, it appears that potential opportunity remains for the identification of a FAK and Pyk2 inhibitor that is capable of reaching brain tumors behind the BBB.
TGFβ-R
ARTICLE SECTIONS
Inhibition of transforming growth factor receptor β (TGFβ-R) kinase activity has been identified as a potential mechanism to treat glioblastoma.(296) The TGF-β inhibitors galunisertib and TEW-7197 (structure not disclosed) have been reported to have advanced to clinical trials.(297) However, considerations of brain penetration are not reported for these molecules.
PIM1 Kinase
ARTICLE SECTIONS
PIM1 kinase has been identified as a potential target for the treatment of GBM.(298) The PIM inhibitors N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (SGI-1776),(299)N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (LGH447),(300) and (R,Z)-5-((2-(3-aminopiperidin-1-yl)-[1,1′-biphenyl]-3-yl)methylene)thiazolidine-2,4-dione (AZD-1208)(301) have advanced to clinical trials, but we were unable to identify data suggesting whether or not these molecules are substrates of efflux transport or are capable of freely penetrating the BBB.
BTK
ARTICLE SECTIONS
Ibrutinib (124)(302) (Table 21) is an inhibitor of Bruton’s tyrosine kinase (BTK) that has been approved for use in some hematological cancers including mantle cell lymphoma (MCL). While rare, CNS metastases can arise in patients with MCL. In a small study, each of three patients with CNS involvement in MCL responded to ibrutinib (two with complete response of CNS lesions).(303) Futhermore, in the two patients evaluated, concentrations in the CSF were significant and expected to be efficacious. The CSF-to-blood ratios ranged from 1% to 7%, but free plasma concentrations would likely indicate a greater free percentage of CNS penetration. Consistent with the free exposure in the CSF, ibrutinib is reported to not be a substrate of P-gp,(304) an encouraging aspect of this molecule for the treatment, or prevention, of CNS progression of hematological malignancies for which it is used.
Other Kinases
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Numerous other kinases have been suggested to be of potential interest as targets for the treatment of brain cancer. Ataxia telangiectasia mutated (ATM),(305) Mer, and Axl(306) are among kinases that have been reported as potential targets for brain cancer but for which no discussion of brain penetration for clinical molecules exists or no molecule has advanced to clinical study for brain cancer treatment.
Conclusion
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In the above sections, the availability of data suggesting whether or not kinase inhibitors of various targets have the potential for free CNS penetration and, therefore, potential in the treatment of brain tumors is discussed. Among the kinases examined here that have a biological rationale to be targeted with inhibitors for the treatment of brain cancers, a distinct minority have CNS penetrant inhibitors that have advanced to clinical study (Table 22). Furthermore, while CNS penetrant inhibitors are available for some kinases, their evaluation has not yet concluded, so no conclusion on the validity of the hypotheses of inhibiting their targets to treat brain cancer can yet be drawn.
Table 22. Kinases of Interest for Brain Cancer and Whether or Not CNS Penetrating Clinical Inhibitors Are Available
| kinase targets with CNS penetrant clinical inhibitors available | kinase targets without known CNS penetrant clinical inhibitors |
|---|---|
| EGFR | VEGFR |
| Pl3K/mTOR | AKT |
| CDK4/6 | lGF-1R |
| ALK | CDK1/2 |
| HER2 | b-RAF |
| MEK | PLK1 |
| Abl/Src | Aurora |
| BTK | PKC |
| c-MET | |
| FAK/Pyk2 | |
| TGFR-β | |
| PlM1 | |
| ATM | |
| Mer | |
| AXL | |
| FGFR |
It is important to note that only evidence of free CNS penetration or lack of P-gp/Bcrp transport of clinical inhibitors was considered in determining whether a kinase target has a tool to assess it as a target for treatment of CNS tumors (i.e., its categorization in Table 22). In reality, many other additional variables impact evaluation of a hypothesis clinically (e.g., PK, selectivity profile, safety, extent of free brain penetration, etc.), and so even for targets where CNS penetrant clinical inhibitors are available, lack of benefit may be encountered in the clinic for other reasons. Therefore, for each indicated kinase target discussed here, opportunity may remain for additional or improved inhibitors that are specifically designed to treat brain cancers, even where a brain penetrant inhibitor already exists and for which a known liability might be addressed. The paucity of CNS penetrant kinase inhibitors also limits study of combinations of brain penetrant kinase inhibitors, which may be a necessary treatment approach for certain tumors.(307)
Of the kinase inhibitors included in the above discussion, we identified 68 as having evidently limited CNS penetration (n = 48; molecules that achieve low free or total brain concentrations or are reported substrates of P-gp/Bcrp) or where some CNS penetration was evident/anticipated (n = 20; molecules that achieve meaningul free brain concentrations or are reportedly not substrates of P-gp/Bcrp).(308) In Table 23 we compare the physicochemical properties of kinase inhibitors identified in the discussion above as CNS penetrating to those that have limited CNS penetration, as well as 119 marketed CNS drugs. There is remarkable similarity in the median values of cLogP, cLogD7.4, TPSA, HBD, and MW among the two categories of kinase inhibitors (mean values are also very similar). The only significant differentiation between the two classes of kinase inhibitors was in the calculated pKa category (which can affect HBD count for those sufficiently basic), where CNS penetrating kinase inhibitors have a lower median pKa than either kinase inhibitors that do not cross the BBB or CNS drugs. Possibly affecting the quality of the data set and preventing emergence of additional differentiation in the properties between the groups, however, is a lack of free-brain-to-free-plasma drug concentration ratios for most molecules. That is, perhaps additional data and application of more stringent criteria to designate molecules as CNS penetrating might yield different results. Additionally, as discussed next, there are limitations to the use of calculated physical properties that might conceal actual differences between molecules. Also, while rare, there is a potential for species differences in P-gp to affect the interpretation of reported data.
Table 23. Comparison of Median Values of Physicochemical Properties for Kinase Inhibitors Discussed above That Are (a) Reported or Predicted (Based on Efflux Transport Data) To Have Limited CNS Penetration or (b) Reported To Have Significant Free CNS Penetration and/or No Significant P-gp or Bcrp Effluxa
| kinase inhibitors | |||
|---|---|---|---|
| median property value | limited CNS penetration (n = 48)b | CNS penetrating (n = 20)b | CNS drugs (n = 119)c |
| cLogP | 4.3 | 4.1 | 2.8 |
| cLogD7.4 | 3.3 | 3.4 | 1.7 |
| TPSA (Å2) | 92 | 98 | 45 |
| HBD | 2 | 2 | 1 |
| MW | 479 | 483 | 305 |
| c_pKa | 8.3 | 6.5 | 8.4 |
a
Median values of marketed CNS drugs are included for comparison.
b
Kinase inhibitors CNS penetration categorization assigned based on data in discussions above. A complete list of the kinase inhibitors assigned to each category and their calculated physicochemical properties is provided in Supporting Information.
c
Marketed CNS drugs. Values obtained from ref 12.
There are very few reports of the design of kinase inhibitors specifically for the treatment of brain cancer. We identified only five molecules, 21, 22, 25, 66, and 104, for which achieving brain penetration was a design intent. In the discovery of three of those five molecules (22, 66, and 104), intramolecular hydrogen bonds were utilized to effectively mask at least 1 HBD, which would not be accounted for in the calculated properties of those molecules. Furthermore, such intramolecular hydrogen bonds would also affect effective polar surface area. It is possible that other CNS penetrant kinase inhibitors also, whether intentionally or not, employ such a mechanism to avoid efflux transport to achieve their penetration (e.g., 93 and 97). Regardless, this is an approach that is worth consideration on kinase programs requiring CNS penetration.
As drug discovery programs have increased their appreciation for what consitutes meaningful (free) brain penetration in recent years, the potential for this understanding to impact the discovery of new treatments of brain cancer is evident. Over the previous decades, a large number of kinase inhibitors advanced to clinical study for brain cancer treatment where, given the understanding of CNS penetration available today, negative outcomes were predictable given limited free access of the drug to its target. In fact, such studies should now be considered unjustified.
Treating primary brain tumors with kinase inhibitors requires brain penetrant versions of those molecules and opportunity abounds for the pharmaceutical industry to treat these already significant unmet needs. Additionally, as kinase inhibitors are approved for the treatment of peripheral cancers, the emergence of brain metastases is expected when the treatments are not BBB penetrant (e.g., ALK, HER2, EGFR, etc.). Whereas in discovery programs brain penetration might be considered a liability for potential CNS safety reasons, limiting brain penetration might ultimately result in a resistance mechanism clinically via brain metastasis. In this scenario, best-in-class opportunities may emerge where brain penetrating kinase inhibitors can be realized. Whether for primary brain cancers or brain metastases, that so few kinase inhibitors have been reportedly designed to achieve CNS penetration suggests that the lack of advancement in the treatment of brain cancers has been at least in part due to lack of directed effort with an appreciation of free drug principles. At the same time, that CNS penetrant inhibitors of various kinases have been identified, and specifically designed and realized, demonstrates that success in this area can be achieved, even if the physicochemical properties of kinase inhibitors and those of CNS drugs at first appear at odds. The clear medical need, biological rationale, and improved appreciation for free drug principles provide an impetus and framework to properly approach the challenge of discovering and developing kinase inhibitors for brain cancer.
ARTICLE SECTIONS
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00618.
Calculated physicochemical properties of FDA approved kinase inhibitors and of discussed inhibitors that are capable of penetrating the BBB or have limited CNS penetration (PDF)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Biography
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Timothy P. Heffron
Timothy P. Heffron is a Senior Scientist at Genentech. As a medicinal chemist and chemistry and research team leader, Timothy has contributed to the advancement of programs directed toward treatments for neurooncology, oncology (including cancer immunotherapy), neurology, and ophthalmology indications. Timothy has contributed to seven molecules that have advanced to clinical development, four of which came under his leadership as a chemistry team leader, including taselisib (phase III). Timothy completed his undergraduate studies in chemistry at Yale University and his doctoral studies at The Massachusetts Institute of Technology.
Acknowledgment
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Cyrus Khojasteh, Xingrong Liu, and Alan Olivero are acknowledged for their helpful comments in the preparation of this Perspective.
| GBM | glioblastoma multiforme |
| CNS | central nervous system |
| BBB | blood–brain barrier |
| CSF | cerebral spinal fluid |
| P-gp | P-glycoprotein |
| Bcrp | breast cancer resistance protein |
| HBD | hydrogen bond donor |
| TPSA | topological polar surface area |
| VEGFR | vascular endothelial growth factor receptor |
| PDGFR | platelet derived growth factor receptor |
| EGFR | epidermal growth factor receptor |
| PI3K | phosphoinositide 3-kinase |
| AKT | protein kinase B |
| mTOR | mammalian target of rapamycin |
| HER2 | human epidermal growth factor receptor 2 |
| FGFR | fibroblast growth factor receptor |
| IGF-1R | type I insulin growth factor receptor |
| CDK | cyclin-dependent kinase |
| ALK | anaplastic lymphoma kinase |
| MEK | mitogen activated protein kinase |
| PLK | Polo-like kinase |
| PKC | protein kinase C |
| Ph+ | Philadelphia chromosome positive |
| CML | chronic myeloid leukemia |
| ALL | acute lymphoblastic leukemia |
| FAK | focal-adhesion kinase |
| Pyk2 | proline rich tyrosine kinase 2 |
| TGFβ-R | transforming growth factor receptor β |
| BTK | Bruton’s tyrosine kinase |
| MCL | mantle cell lymphoma |
| ATM | ataxia telangiectasia mutated |
References
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This article references 308 other publications.
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Translational research examg. metastasis to the brain needs to be multi-disciplinary, marrying advanced chem., blood-brain barrier pharmacokinetics, neurocognitive testing and radiation biol. with metastasis biol., to develop and implement new clin. trial designs. Advances in the chemoprevention of brain metastases, the validation of tumor radiation sensitizers and the amelioration of cognitive deficits caused by whole-brain radiation therapy are discussed.(b) Sledge, G. W. Heading in a new direction: drug permeability in breast cancer brain metastasis Clin. Cancer Res. 2010, 16, 5605– 5607 DOI: 10.1158/1078-0432.CCR-10-2502[Crossref], [PubMed], [CAS], Google Scholar6bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M%252Fitl2lsQ%253D%253D&md5=c4bc748744757ff9720aeabdbff16e60Heading in a new direction: drug permeability in breast cancer brain metastasisSledge George W JrClinical cancer research : an official journal of the American Association for Cancer Research (2010), 16 (23), 5605-7 ISSN:1078-0432.Systemic therapies for breast cancer brain metastasis are largely unsuccessful. Mouse models of brain metastasis show significant heterogeneity in uptake of paclitaxel and doxorubicin, with average levels more than those seen in normal brain tissue, but significantly less than in metastases to other organs.(c) Lockman, P. R.; Mittapalli, R. K.; Taskar, K. S.; Rudraraju, V.; Gril, B.; Bohn, K. A.; Adkins, C. E.; Roberts, A.; Thorsheim, H. R.; Gaasch, J. A.; Huang, S.; Palmien, D.; Steeg, P. S.; Smith, Q. R. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer Clin. Cancer Res. 2010, 16, 5664– 5678 DOI: 10.1158/1078-0432.CCR-10-1564[Crossref], [PubMed], [CAS], Google Scholar6chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFamtL3F&md5=f14491d5c3f4a345b4114c348632916cHeterogeneous Blood-Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast CancerLockman, Paul R.; Mittapalli, Rajendar K.; Taskar, Kunal S.; Rudraraju, Vinay; Gril, Brunilde; Bohn, Kaci A.; Adkins, Chris E.; Roberts, Amanda; Thorsheim, Helen R.; Gaasch, Julie A.; Huang, Suyun; Palmieri, Diane; Steeg, Patricia S.; Smith, Quentin R.Clinical Cancer Research (2010), 16 (23), 5664-5678CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)PURPOSE: Brain metastases of breast cancer appear to be increasing in incidence, confer significant morbidity, and threaten to compromise gains made in systemic chemotherapy. The blood-tumor barrier (BTB) is compromised in many brain metastases; however, the extent to which this influences chemotherapeutic delivery and efficacy is unknown. Herein, we answer this question by measuring BTB passive integrity, chemotherapeutic drug uptake, and anticancer efficacy in vivo in two breast cancer models that metastasize preferentially to brain. Exptl. Design:Exptl. brain metastasis drug uptake and BTB permeability were simultaneously measured using novel fluorescent and phosphorescent imaging techniques in immune-compromised mice. Drug-induced apoptosis and vascular characteristics were assessed using immunofluorescent microscopy. RESULTS: Anal. of over 2,000 brain metastases from two models (human 231-BR-Her2 and murine 4T1-BR5) showed partial BTB permeability compromise in greater than 89% of lesions, varying in magnitude within and between metastases. Brain metastasis uptake of 14C-paclitaxel and 14C-doxorubicin was generally greater than normal brain but less than 15% of that of other tissues or peripheral metastases, and only reached cytotoxic concns. in a small subset (∼10%) of the most permeable metastases. Neither drug significantly decreased the exptl. brain metastatic ability of 231-BR-Her2 tumor cells. BTB permeability was assocd. with vascular remodeling and correlated with overexpression of the pericyte protein desmin. CONCLUSIONS: This work shows that the BTB remains a significant impediment to std. chemotherapeutic delivery and efficacy in exptl. brain metastases of breast cancer. New brain permeable drugs will be needed. Evidence is presented for vascular remodeling in BTB permeability alterations. Clin Cancer Res; 16(23); 5664-78.(d) Henson, J. W.; Cordon-Cardo, C.; Posner, J. B. P-glycoprotein expression in brain tumors J. Neuro-Oncol. 1992, 14, 37– 43 DOI: 10.1007/BF00170943[Crossref], [PubMed], [CAS], Google Scholar6dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3s7gvVSguw%253D%253D&md5=be90a5093bf829cba5e21c4a5a5eb321P-glycoprotein expression in brain tumorsHenson J W; Cordon-Cardo C; Posner J BJournal of neuro-oncology (1992), 14 (1), 37-43 ISSN:0167-594X.Overexpression of P-glycoprotein (P-gp) in cancer cells can result in resistance to several chemotherapy agents (multidrug resistance) including doxorubicin and vincristine. The drugs to which resistance develops also penetrate the blood brain barrier poorly. P-gp expression in brain capillary endothelial cells suggests that P-gp may restrict drug entry into brain tumors and thus be another mechanism of drug resistance. To seek evidence for either of these roles in the drug resistance of brain tumors, we examined the location of expression of P-gp in 49 brain tumors, using an anti-P-gp mouse monoclonal antibody and immunohistochemistry. P-gp expression was observed in tumor cells of two glioblastomas and a meningeal sarcoma but not in low-grade primary or metastatic tumors. In low-grade primary tumors, P-gp was present in all vascular endothelial cells. In the vascular endothelial cells of anaplastic primary brain tumors and brain metastases, P-gp expression was heterogeneous or absent. These findings are consistent with a role for P-gp in the resistance of some brain tumors to chemotherapy agents.(e) Demeule, M.; Shedid, D.; Beaulieu, E.; Del Maestro, R. F.; Moghrabi, A.; Ghosn, P. B.; Moumdijian, R.; Berthelet, F.; Beliveau, R. Expression of multidrug-resistance P-glycoprotein (MDR1) in human brain tumors Int. J. Cancer 2001, 93, 62– 66 DOI: 10.1002/ijc.1306[Crossref], [PubMed], [CAS], Google Scholar6ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXksFanur0%253D&md5=de070fb54c77cf4a556f8c581e27295dExpression of multidrug-resistance P-glycoprotein (MDR1) in human brain tumorsDemeule, Michel; Shedid, Daniel; Beaulieu, Edith; Del Maestro, Rolando F.; Moghrabi, Albert; Ghosn, Pierre B.; Moumdjian, Robert; Berthelet, France; Beliveau, RichardInternational Journal of Cancer (2001), 93 (1), 62-66CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)Multidrug resistance (MDR) is assocd. with the expression of P-glycoprotein (P-gp), an ATP-dependent transporter which expels anti-cancer drugs from cells. In the present study, MDR1 P-gp was immunodetected by Western blot anal. in 60 human brain tumors, including meningiomas, schwannomas, low-grade gliomas (astrocytomas, pilocytic astrocytomas) and high-grade gliomas (anaplastic astrocytomas, glioblastomas and anaplastic oligodendrogliomas). Most samples from primary tumors expressed P-gp at the same levels as normal brain tissue except for schwannomas, in which levels were reduced by 65%, and meningiomas, in which levels were more than 10-fold higher in 7 of 10 samples. P-gp levels were 70% and 95% lower in brain metastases from melanomas and lung adenocarcinomas, resp., than in normal brain tissue. These results indicate that the majority of primary brain tumors express MDR1 P-gp and that its high expression levels in meningiomas may be a marker for this type of brain tumor.
- 7(a) Claes, A.; Idema, A. J.; Wesseling, P. Diffuse glioma growth: a guerrila war Acta Neuropathol. 2007, 114, 443– 448 DOI: 10.1007/s00401-007-0293-7[Crossref], [PubMed], [CAS], Google Scholar7ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2srovFamuw%253D%253D&md5=41a660215dccbe502b7fabf5b04867baDiffuse glioma growth: a guerilla warClaes An; Idema Albert J; Wesseling PieterActa neuropathologica (2007), 114 (5), 443-58 ISSN:0001-6322.In contrast to almost all other brain tumors, diffuse gliomas infiltrate extensively in the neuropil. This growth pattern is a major factor in therapeutic failure. Diffuse infiltrative glioma cells show some similarities with guerilla warriors. Histopathologically, the tumor cells tend to invade individually or in small groups in between the dense network of neuronal and glial cell processes. Meanwhile, in large areas of diffuse gliomas the tumor cells abuse pre-existent "supply lines" for oxygen and nutrients rather than constructing their own. Radiological visualization of the invasive front of diffuse gliomas is difficult. Although the knowledge about migration of (tumor)cells is rapidly increasing, the exact molecular mechanisms underlying infiltration of glioma cells in the neuropil have not yet been elucidated. As the efficacy of conventional methods to fight diffuse infiltrative glioma cells is limited, a more targeted ("search & destroy") tactic may be needed for these tumors. Hopefully, the study of original human glioma tissue and of genotypically and phenotypically relevant glioma models will soon provide information about the Achilles heel of diffuse infiltrative glioma cells that can be used for more effective therapeutic strategies.(b) Agarwal, S.; Sane, R.; Oberoi, R.; Ohlfest, J. R.; Elmquist, W. F. Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain Expert Rev. Mol. Med. 2011, 13, e17 DOI: 10.1017/S1462399411001888[Crossref], [PubMed], [CAS], Google Scholar7bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXms1OksLw%253D&md5=64ddd4cf91c94640ec2d1e548924383cDelivery of molecularly targeted therapy to malignant glioma, a disease of the whole brainAgarwal, Sagar; Sane, Ramola; Oberoi, Rajneet; Ohlfest, John R.; Elmquist, William F.Expert Reviews in Molecular Medicine (2011), 13 (), e17/1-e17/17CODEN: ERMMFS; ISSN:1462-3994. (Cambridge University Press)A review. Glioblastoma multiforme, because of its invasive nature, can be considered a disease of the entire brain. Despite recent advances in surgery, radiotherapy and chemotherapy, current treatment regimens have only a marginal impact on patient survival. A crucial challenge is to deliver drugs effectively to invasive glioma cells residing in a sanctuary within the central nervous system. The blood-brain barrier (BBB) restricts the delivery of many small and large mols. into the brain. Drug delivery to the brain is further restricted by active efflux transporters present at the BBB. Current clin. assessment of drug delivery and hence efficacy is based on the measured drug levels in the bulk tumor mass that is usually removed by surgery. Mounting evidence suggests that the inevitable relapse and lethality of glioblastoma multiforme is due to a failure to effectively treat invasive glioma cells. These invasive cells hide in areas of the brain that are shielded by an intact BBB, where they continue to grow and give rise to the recurrent tumor. Effective delivery of chemotherapeutics to the invasive glioma cells is therefore crit., and long-term efficacy will depend on the ability of a molecularly targeted agent to penetrate an intact and functional BBB throughout the entire brain. This review highlights the various aspects of the BBB, and also the brain-tumor-cell barrier (a barrier due to expression of efflux transporters in tumor cells), that together can significantly influence drug response. It then discusses the challenge of glioma as a disease of the whole brain, which lends emphasis to the need to deliver drugs effectively across the BBB to reach both the central tumor and the invasive glioma cells.(c) Kuratsu, J.; Itoyama, Y.; Uemura, S.; Ushio, Y. Regrowth patterns of glioma—cases of glioma regrew away from the original tumor Gan No Rinsho 1989, 35, 1255– 1260[PubMed], [CAS], Google Scholar7chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3c%252FktFemsw%253D%253D&md5=079ef2db2deab51b57f353b53d2db65aRegrowth patterns of glioma--cases of glioma regrew away from the original tumorKuratsu J; Itoyama Y; Uemura S; Ushio YGan no rinsho. Japan journal of cancer clinics (1989), 35 (11), 1255-60 ISSN:0021-4949.There have been conflicting opinions regarding the correct volume to be used in radiotherapy fields for malignant glioma. Whereas many clinicians recommend limited fields designed to cover the tumor volume with a margin according to the facts about 90% of recurrent malignant glioma regrew within 2 cm of the original tumor and regrowth away from the original tumor was seen in about 5%. Two cases of malignant glioma regrew away for the original tumor and one case of malignant glioma regrew into the resected site were presented. And the biological characteristics of glioma cells concerning with the invasiveness were discussed.(d) Silbergeld, D. L.; Chicoine, M. R. Isolation and characterization of human malignant glioma cells from histologically normal brain J. Neurosurg. 1997, 86, 525– 531 DOI: 10.3171/jns.1997.86.3.0525[Crossref], [PubMed], [CAS], Google Scholar7dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s7pvVamtQ%253D%253D&md5=922c50772af913db88f8112415eabd16Isolation and characterization of human malignant glioma cells from histologically normal brainSilbergeld D L; Chicoine M RJournal of neurosurgery (1997), 86 (3), 525-31 ISSN:0022-3085.Brain invasion prevents complete surgical extirpation of malignant gliomas; however, invasive cells from distant, histologically normal brain previously have not been isolated, cultured, and characterized. To evaluate invasive human malignant glioma cells, the authors established cultures from gross tumor and histologically normal brain. Three men and one woman, with a mean age of 67 years, underwent two frontal and two temporal lobectomies for tumors, which yielded specimens of both gross tumor and histologically normal brain. Each specimen was acquired a minimum of 4 cm from the gross tumor. The specimens were split: a portion was sent for neuropathological evaluation (three glioblastomas multiforme and one oligodendroglioma) and a portion was used to establish cell lines. Morphologically, the specimens of gross tumor and histologically normal brain were identical in three of the four cell culture pairs. Histochemical staining characteristics were consistent both within each pair and when compared with the specimens sent for neuropathological evaluation. Cultures demonstrated anchorage-independent growth in soft agarose and neoplastic karyotypes. Growth rates in culture were greater for histologically normal brain than for gross tumor in three of the four culture pairs. Although the observed increases in growth rates of histologically normal brain cultures do not correlate with in vivo behavior, these findings corroborate the previously reported stem cell potential of invasive glioma cells. Using the radial dish assay, no significant differences in motility between cultures of gross tumor and histologically normal brain were found. In summary, tumor cells were cultured from histologically normal brain acquired from a distance greater than 4 cm from the gross tumor, indicating the relative insensitivity of standard histopathological identification of invasive glioma cells (and hence the inadequacy of frozen-section evaluation of resection margins). Cell lines derived from gross tumor and histologically normal brain were usually histologically identical and demonstrated equivalent motility, but had different growth rates.(e) Lucio-Eterovic, A. K.; Piao, Y.; de Groot, J. F. Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy Clin. Cancer Res. 2009, 15, 4589– 4599 DOI: 10.1158/1078-0432.CCR-09-0575[Crossref], [PubMed], [CAS], Google Scholar7ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosV2lt7Y%253D&md5=804ce893168284aa1a95abac77e8b92cMediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapyLucio-Eterovic, Agda K.; Piao, Yuji; de Groot, John F.Clinical Cancer Research (2009), 15 (14), 4589-4599CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)PURPOSE: Vascular endothelial growth factor (VEGF) has been identified as a crit. regulator of angiogenesis. Currently, several different strategies are being used to target the VEGF-VEGF receptor signal transduction pathway in glioblastoma. Although anti-VEGF therapy seems be effective in normalizing abnormal tumor vasculature, leading to an enhanced response to radiation and chemotherapy, tumors eventually become resistant to the therapy and adopt a highly infiltrative and invasive phenotype. Exptl. Design: In the present study, we evaluated the effects of anti-VEGF therapy (bevacizumab) on glioblastoma invasion both in vitro and in vivo and evaluated the angiogenesis- and invasion-related mediators of developed resistance to this therapy. RESULTS: We found that glioblastoma tumors escaped from antiangiogenic treatment by (a) reactivating angiogenesis through up-regulation of other proangiogenic factors and (b) invading normal brain areas, which was seen in assocn. with up-regulation of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-12; secreted protein, acidic, cysteine-rich; and tissue inhibitor of metalloproteinase 1. In addn. to the paracrine effects of VEGF on endothelial cells, autocrine VEGF signaling seemed to regulate glioblastoma invasion because anti-VEGF therapy increased tumor invasiveness in vitro. CONCLUSIONS: Collectively, these findings reinforce the importance of VEGF in regulating tumor invasion and identify potential mediators of resistance to targeted VEGF therapy. These results will be important for developing novel combination therapies to overcome this resistance phenotype.
- 8Rankovic, Z. CNS Drug Design: Balancing physicochemical properties for optimal brain exposure J. Med. Chem. 2015, 58, 2584– 2608 DOI: 10.1021/jm501535r[ACS Full Text
], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVyhsrrP&md5=f01e3f2dc4e2eff7b0618124277a5cf8CNS Drug Design: Balancing Physicochemical Properties for Optimal Brain ExposureRankovic, ZoranJournal of Medicinal Chemistry (2015), 58 (6), 2584-2608CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing mols. that can overcome this protection system and achieve optimal concn. at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochem. properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most crit. physicochem. and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chem. strategies toward mols. with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided. - 9Levin, V. A.; Tonge, P. T.; Gallo, J. M.; Birtwistle, M. R.; Dar, A. C.; Iavarone, A.; Paddison, P. J.; Heffron, T. P.; Elmquist, W. F.; Lachowicz, J. E.; Johnson, T. W.; White, F. M.; Sul, J.; Smith, Q. R.; Shen, W.; Sarkaria, J. N.; Samala, R.; Wen, P. Y.; Berry, D. A.; Petter, R. C. CNS anticancer drug discovery and development conference white paper Neuro-Oncology 2015, 17, vi1– vi26 DOI: 10.1093/neuonc/nov169
- 10(a) Sun, H.; Dai, H.; Shaik, N.; Elmquist, W. F. Drug efflux transporters in the CNS Adv. Drug Delivery Rev. 2003, 55, 83– 105 DOI: 10.1016/S0169-409X(02)00172-2(b) He, H.; Lyons, K. A.; Shen, X.; Yao, Z.; Bleasby, K.; Chan, G.; Hafey, M.; Li, X.; Xu, S.; Salituro, G. M.; Cohen, L. H.; Tang, W. Utility of unbound plasma drug levels and P-glycoprotein transport data in prediction of central nervous system exposure Xenobiotica 2009, 39, 687– 693 DOI: 10.1080/00498250903015402[Crossref], [PubMed], [CAS], Google Scholar10bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXps12gtbs%253D&md5=f9b7ad759a8ced86e9b8b90c445217f3Utility of unbound plasma drug levels and P-glycoprotein transport data in prediction of central nervous system exposureHe, H.; Lyons, K. A.; Shen, X.; Yao, Z.; Bleasby, K.; Chan, G.; Hafey, M.; Li, X.; Xu, S.; Salituro, G. M.; Cohen, L. H.; Tang, W.Xenobiotica (2009), 39 (9), 687-693CODEN: XENOBH; ISSN:0049-8254. (Informa Healthcare)Drug concns. in cerebrospinal fluid were assumed to be a natural surrogate for total drug exposures in the central nervous system. The present communication reports a data set from a study of 30 compds. in mice. An attempt was made to correlate cerebrospinal fluid and unbound plasma drug concns. via incorporation of in vitro P-glycoprotein (Pgp)-mediated transport data. Pgp-deficient (Pgp -/-) and wild-type mice were dosed with compds. of interest by oral gavage (orally) at 5 mg kg-1. Plasma and cerebrospinal fluid samples were collected at 1h post-dosing, and analyzed by liq. chromatog.-tandem mass spectrometry (LC-MS/MS) for drug concns. Mouse and human Pgp-mediated transport were evaluated in vitro by a bi-directional (B to A and A to B) transport assay using LLC-PK1 cells expressing mouse (mdr1a) and human (MDR1) forms of Pgp, resp. Compds. with B to A/A to B transport ratios <2 were defined as non-substrates of Pgp, whereas those exhibiting B to A/A to B transport ratios ≥2 were considered Pgp substrates. Plasma protein binding was also detd. in vitro via equil. dialysis. Of the 30 compds., 13 were identified to be mouse Pgp substrates, all of which were also human Pgp substrates, demonstrating a good agreement between mouse and human data. In Pgp wild-type mice, the unbound plasma and cerebrospinal fluid concns. of the non-Pgp substrates correlated well, with a regression slope of approx. 1.0. A similar relationship existed for Pgp substrates in Pgp -/- mice. On the other hand, an improved correlation of cerebrospinal fluid and systemic exposures of the Pgp substrates in Pgp wild-type mice was obsd. when the unbound plasma concns. were normalized to the corresponding B to A/A to B transport ratios. These results reinforce the premise that a combined use of unbound plasma drug concns. and in vitro Pgp transport data may be of value for the estn. of central nervous system exposures.(c) Kodaira, H.; Kusuhara, H.; Fujita, T.; Ushiki, J.; Fuse, E.; Sugiyama, Y. Quantitative evaluation of the impact of active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a surrogate J. Pharmacol. Exp. Ther. 2011, 339, 935– 944 DOI: 10.1124/jpet.111.180398[Crossref], [PubMed], [CAS], Google Scholar10chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtVSksbo%253D&md5=36a778b164943b101534146120fc6cdfQuantitative evaluation of the impact of active efflux by P-glycoprotein and breast cancer resistance protein at the blood-brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a surrogateKodaira, Hiroshi; Kusuhara, Hiroyuki; Fujita, Takuya; Ushiki, Junko; Fuse, Eiichi; Sugiyama, YuichiJournal of Pharmacology and Experimental Therapeutics (2011), 339 (3), 935-944CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)This study investigated the impact of the active efflux mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) at the blood-brain barrier (BBB) on the predictability of the unbound brain concn. (Cu,brain) by the concn. in the cerebrospinal fluid (CSF) (Cu,CSF) in rats. Cu,brain is obtained as the product of the total brain concn. and unbound fraction in the brain (fu,brain) detd. in vitro in brain slices. Twenty-five compds., including P-gp and/or Bcrp substrates, were given a const. i.v. infusion, and their plasma, brain, and CSF concns. were detd. P-gp and/or Bcrp substrates, such as verapamil, loperamide, flavopiridol, genistein, quinidine, dantrolene, daidzein, cimetidine, and pefloxacin, showed a higher CSF-to-brain unbound concn. ratio (Kp,uu,CSF/brain) compared with non-P-gp and non-Bcrp substrates. Kp,uu,CSF/brain values of P-gp-specific (quinidine and verapamil) and Bcrp-specific (daidzein and genistein) substrates were significantly decreased in Mdr1a/1b(-/-) and Bcrp(-/-) mice, resp. Furthermore, consistent with the contribution of P-gp and Bcrp to the net efflux at the BBB, Kp,uu,CSF/brain values of the common substrates (flavopiridol and erlotinib) were markedly decreased in Mdr1a/1b(-/-)/Bcrp(-/-) mice, but only moderately or weakly in Mdr1a/1b(-/-) mice and negligibly in Bcrp(-/-) mice. In conclusion, predictability of Cu,brain by Cu,CSF decreases along with the net transport activities by P-gp and Bcrp at the BBB. Cu,CSF of non-P-gp and non-Bcrp substrates can be a reliable surrogate of Cu,brain for lipophilic compds.
- 11Zuccotto, F.; Ardini, E.; Casale, E.; Angiolini, M. Through the “gatekeeper door”: exploiting the active kinase conformation J. Med. Chem. 2010, 53, 2681– 2694 DOI: 10.1021/jm901443h[ACS Full Text], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFGhtb3K&md5=5c6acd058bacfec89b1eff2090f0fe67Through the "Gatekeeper Door": Exploiting the Active Kinase ConformationZuccotto, Fabio; Ardini, Elena; Casale, Elena; Angiolini, MauroJournal of Medicinal Chemistry (2010), 53 (7), 2681-2694CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The development of new kinase inhibitors is still a slow and problematic process. Generally, type I compds. suffer from widespread cross-reactivity among other members of the kinase target family, and intense medicinal chem. optimization programs are required to modulate their activity. Also, fierce competition in the development of scaffolds that could mimic ATP has led to a crowded intellectual property space. The new opportunities opened by the type II compds. created great expectations, as targeting the allosteric site of the ATP pocket offered addnl. opportunities to control selectivity and introduce intellectual property novelty. However, clin. evaluation of these compds. has highlighted how the acquisition of resistance-causing mutations of the kinase target limits their efficacy in cancer treatment.
- 12(a) Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes ACS Chem. Neurosci. 2010, 1, 420– 434 DOI: 10.1021/cn100007x[ACS Full Text], [CAS], Google Scholar12ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjvVaqtbk%253D&md5=85716be86290fd85e93c6b8d5621683cDefining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety AttributesWager, Travis T.; Chandrasekaran, Ramalakshmi Y.; Hou, Xinjun; Troutman, Matthew D.; Verhoest, Patrick R.; Villalobos, Anabella; Will, YvonneACS Chemical Neuroscience (2010), 1 (6), 420-434CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)As part of our effort to increase survival of drug candidates and to move our medicinal chem. design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) mols. We carried out a thorough anal. of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular, we focused on understanding the relationships between physicochem. properties, in vitro ADME (absorption, distribution, metab., and elimination) attributes, primary pharmacol. binding efficiencies, and in vitro safety data for these two sets of compds. This scholarship provides guidance for the design of CNS mols. in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic.(b) Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties ACS Chem. Neurosci. 2010, 1, 435– 449 DOI: 10.1021/cn100008c[ACS Full Text], [CAS], Google Scholar12bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjvVejtr8%253D&md5=e94998f65a420be6ee4dec4a987cb983Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike PropertiesWager, Travis T.; Hou, Xinjun; Verhoest, Patrick R.; Villalobos, AnabellaACS Chemical Neuroscience (2010), 1 (6), 435-449CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)The interplay among commonly used physicochem. properties in drug design was examd. and utilized to create a prospective design tool focused on the alignment of key druglike attributes. Using a set of six physicochem. parameters ((a) lipophilicity, calcd. partition coeff. (ClogP); (b) calcd. distribution coeff. at pH = 7.4 (ClogD); (c) mol. wt. (MW); (d) topol. polar surface area (TPSA); (e) no. of hydrogen bond donors (HBD); (f) most basic center (pKa)), a druglikeness central nervous system multiparameter optimization (CNS MPO) algorithm was built and applied to a set of marketed CNS drugs (N = 119) and Pfizer CNS candidates (N = 108), as well as to a large diversity set of Pfizer proprietary compds. (N = 11 303). The novel CNS MPO algorithm showed that 74% of marketed CNS drugs displayed a high CNS MPO score (MPO desirability score ≥ 4, using a scale of 0-6), in comparison to 60% of the Pfizer CNS candidates. This anal. suggests that this algorithm could potentially be used to identify compds. with a higher probability of successfully testing hypotheses in the clinic. In addn., a relationship between an increasing CNS MPO score and alignment of key in vitro attributes of drug discovery (favorable permeability, P-glycoprotein (P-gp) efflux, metabolic stability, and safety) was seen in the marketed CNS drug set, the Pfizer candidate set, and the Pfizer proprietary diversity set. The CNS MPO scoring function offers advantages over hard cutoffs or utilization of single parameters to optimize structure-activity relationships (SAR) by expanding medicinal chem. design space through a holistic assessment approach. Based on six physicochem. properties commonly used by medicinal chemists, the CNS MPO function may be used prospectively at the design stage to accelerate the identification of compds. with increased probability of success.
- 13(a)Wu, P.; Nielsen, T. E.; Clausen, M. H. FDA-approved small-molecule kinase inhibitors Trends Pharmacol. Sci. 2015, 36, 422– 439 DOI: 10.1016/j.tips.2015.04.005
For inhibitors approved through 2014:
[Crossref], [PubMed], [CAS], Google Scholar13ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXns1KisLg%253D&md5=a6aa3dbb11e6fe3001fa5fa03a4c950aFDA-approved small-molecule kinase inhibitorsWu, Peng; Nielsen, Thomas E.; Clausen, Mads H.Trends in Pharmacological Sciences (2015), 36 (7), 422-439CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)A review. Kinases have emerged as one of the most intensively pursued targets in current pharmacol. research, esp. for cancer, due to their crit. roles in cellular signaling. To date, the US FDA has approved 28 small-mol. kinase inhibitors, half of which were approved in the past 3 years. While the clin. data of these approved mols. are widely presented and structure-activity relationship (SAR) has been reported for individual mols., an updated review that analyzes all approved mols. and summarizes current achievements and trends in the field has yet to be found. Here we present all approved small-mol. kinase inhibitors with an emphasis on binding mechanism and structural features, summarize current challenges, and discuss future directions in this field.(b)http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm430302.htm (accessed June 12, 2016) .For inhibitors approved in 2015:
- 14Bridges, A. J. Chemical inhibitors of protein kinases Chem. Rev. 2001, 101, 2541– 2572 DOI: 10.1021/cr000250y[ACS Full Text], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXkvVWnt7k%253D&md5=05ee78880cc9dcf485684e05327108dbChemical inhibitors of protein kinasesBridges, Alexander J.Chemical Reviews (Washington, D. C.) (2001), 101 (8), 2541-2571CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review with 258 refs. on development protein kinase inhibitors as potential antitumor agents.
- 15Cole, S.; Bagal, S.; El-Kattan, A.; Fenner, K.; Hay, T.; Kempshall, S.; Lunn, G.; Varma, M.; Stupple, P.; Speed, W. Full efficacy with no CNS side-effects: unachievable panacea or reality? DMPK considerations in design of drugs with limited brain penetration Xenobiotica 2012, 42, 11– 27 DOI: 10.3109/00498254.2011.617847
- 16Huszthy, P. C.; Daphu, I.; Niclou, S. P.; Stieber, D.; Nigro, J. M.; Sakariassen, P.; Miletic, H.; Thorsen, F.; Bjerkvig, R. In vivo models of primary brain tumors: pitfalls and perspectives Neuro-Oncology 2012, 14, 979– 993 DOI: 10.1093/neuonc/nos135
- 17Lee, J.; Kotilarova, S.; Kotliarov, Y.; Li, A.; Su, Q.; Donin, N. M.; Pastorino, S.; Purow, B. W.; Christopher, N.; Zhang, W.; Park, J. K.; Fine, H. A. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines Cancer Cell 2006, 9, 391– 403 DOI: 10.1016/j.ccr.2006.03.030[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XltF2nsLk%253D&md5=d558401715c41e3161463bd475281eaaTumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell linesLee, Jeongwu; Kotliarova, Svetlana; Kotliarov, Yuri; Li, Aiguo; Su, Qin; Donin, Nicholas M.; Pastorino, Sandra; Purow, Benjamin W.; Christopher, Neil; Zhang, Wei; Park, John K.; Fine, Howard A.Cancer Cell (2006), 9 (5), 391-403CODEN: CCAECI; ISSN:1535-6108. (Cell Press)The concept of tumor stem cells (TSCs) provides a new paradigm for understanding tumor biol., although it remains unclear whether TSCs will prove to be a more robust model than traditional cancer cell lines. We demonstrate marked phenotypic and genotypic differences between primary human tumor-derived TSCs and their matched glioma cell lines. Unlike the matched, traditionally grown tumor cell lines, TSCs derived directly from primary glioblastomas harbor extensive similarities to normal neural stem cells and recapitulate the genotype, gene expression patterns, and in vivo biol. of human glioblastomas. These findings suggest that TSCs may be a more reliable model than many commonly utilized cancer cell lines for understanding the biol. of primary human tumors.
- 18Jain, R. K.; di Tomaso, E.; Duda, D. G.; Loeffler, J. S.; Sorensen, A. G.; Batchelor, T. T. Angiogenesis in brain tumors Nat. Rev. Neurosci. 2007, 8, 610– 622 DOI: 10.1038/nrn2175[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnvFKntbk%253D&md5=a7effefbdf690ed77822f1aa2342c91fAngiogenesis in brain tumorsJain, Rakesh K.; di Tomaso, Emmanuelle; Duda, Dan G.; Loeffler, Jay S.; Sorensen, A. Gregory; Batchelor, Tracy T.Nature Reviews Neuroscience (2007), 8 (8), 610-622CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)A review. Despite aggressive surgery, radiotherapy and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumors stimulate the formation of new blood vessels through processes driven primarily by vascular endothelial growth factor (VEGF). However, the resulting vessels are structurally and functionally abnormal, and contribute to a hostile microenvironment (low oxygen tension and high interstitial fluid pressure) that selects for a more malignant phenotype with increased morbidity and mortality. Emerging preclin. and clin. data indicate that anti-VEGF therapies are potentially effective in glioblastoma - the most frequent primary brain tumor - and can transiently normalize tumor vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.
- 19(a) Huang, H.; Held-Feindt, J.; Buhl, R.; Mehdorn, H. M.; Mentlein, R. Expression of VEGF and its receptors in different brain tumors Neurol. Res. 2005, 27, 371– 377 DOI: 10.1179/016164105X39833[Crossref], [PubMed], [CAS], Google Scholar19ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlslemsL8%253D&md5=139fa78457bfdfcbc07d4d03f4ba9cf7Expression of VEGF and its receptors in different brain tumorsHuang, Hongguang; Held-Feindt, Janka; Buhl, Ralf; Mehdorn, Hubertus M.; Mentlein, RolfNeurological Research (2005), 27 (4), 371-377CODEN: NRESDZ; ISSN:0161-6412. (Maney Publishing)Introduction: Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and -2 are considered to play a major in tumor angiogenesis, which is a prerequisite for growth of solid tumors. Glioblastoma multiforme is a prominent example of VEGF-induced tumor vascularization; however, little is known about VEGF and in particular VEGFR expression in other types of brain tumors. Methods: VEGFR mRNA was quantified by real time RT-PCR in 12 different types of brain tumors and compared to VEGF protein content measured by ELISA. VEGF splice variants were detd. by an RT-PCR method. Results: VEGF protein was highest in glioblastoma and metastatic kidney tumors. In all types of tumors the diffusible splice forms VEGF121 and VEGF165 were expressed; VEGF189 was minor in a few tumors. Expression of VEGF receptors did not necessarily correlate with VEGF content. Both were highly expressed in glioblastomas, but in meningiomas VEGF was low and VEGFR high, and in metastatic tumors the reverse. With few exceptions, in particular oligodendrogliomas, VEGFR-1 expression was parallel to VEGFR-2 expression. Interestingly, for the astrocytic gliomas, the expression of VEGFR correlated well to the tumor malignancy, even better than VEGF content. Conclusions: These results show that VEGF and VEGFR expression in various types of brain tumors differ and are not necessarily parallel.(b) Tuettenberg, J.; Friedel, C.; Vajkoczy, P. Angiogenesis in malignant glioma-a target for antitumor therapy? Crit. Rev. Oncol. Hematol. 2006, 59, 181– 193 DOI: 10.1016/j.critrevonc.2006.01.004[Crossref], [PubMed], [CAS], Google Scholar19bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28rhtVGqsw%253D%253D&md5=e2c5eb854b68b1d142b3cfc6ef4ab395Angiogenesis in malignant glioma--a target for antitumor therapy?Tuettenberg J; Friedel C; Vajkoczy PCritical reviews in oncology/hematology (2006), 59 (3), 181-93 ISSN:1040-8428.The prognosis of malignant gliomas is still dismal despite aggressive treatment attempts. Thus, alternative therapy strategies are needed. Malignant gliomas are upon the best vascularized tumors in humans and their proliferation is hallmarked by a distinct proliferative vascular component. Hence it seems to be a logical consequence to apply anti-angiogenic treatment strategies to malignant gliomas. These treatment strategies have shown promising effects in animal models and some experimental clinical studies. This review gives a short introduction into the molecules involved in angiogenesis of malignant gliomas, it provides an overview of the latest experimental developments of glioma angiogenesis inhibition and discusses the results of clinical anti-angiogenic trials in patients with high grade glioma. Additionally the problem of monitoring the treatment success of an anti-angiogenic therapy is addressed.
- 20Barrios, C. H.; Viola, F. S.; Coutinho, L. M.; Paglioli, E. Determination of expression of platelet derived growth factor receptors (PDGFR) in astrocytic tumors J. Clin. Oncol. 2006, 24 (Suppl.) 11518
- 21Wedge, S. R.; Kendrew, J.; Hennequin, L. F.; Valentine, P. J.; Barry, S. J.; Brave, S. R.; Smith, N. R.; James, N. H.; Dukes, M.; Curwen, J. O.; Chester, R.; Jackson, J. A.; Boffey, S. J.; Kilburn, L. L.; Barnett, S.; Richmond, G. H. P.; Wadsworth, P. F.; Walker, M.; Bigley, A. L.; Taylor, S. T.; Cooper, L.; Beck, S.; Jurgensmeier, J. M.; Ogilvie, D. J. AZD2171: A highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer Cancer Res. 2005, 65, 4389– 4400 DOI: 10.1158/0008-5472.CAN-04-4409
- 22Harris, P. A.; Boloor, A.; Cheung, M.; Kumar, R.; Crosby, R. M.; Davis-Ward, R. G.; Epperly, A. H.; Hinkle, K. W.; Hunter, R. N.; Johnson, J. H.; Knick, V. B.; Laudeman, C. P.; Luttrell, D. K.; Mook, R. A.; Nolte, R. T.; Rudolph, S. K.; Szewczyk, J. R.; Truesdale, A. T.; Veal, J. M.; Wang, L.; Stafford, J. A. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor J. Med. Chem. 2008, 51, 4632– 4640 DOI: 10.1021/jm800566m[ACS Full Text], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosVGrtL4%253D&md5=a8737a6e003a3f6002575b4b96712fc9Discovery of 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a Novel and Potent Vascular Endothelial Growth Factor Receptor InhibitorHarris, Philip A.; Boloor, Amogh; Cheung, Mui; Kumar, Rakesh; Crosby, Renae M.; Davis-Ward, Ronda G.; Epperly, Andrea H.; Hinkle, Kevin W.; Hunter, Robert N., III; Johnson, Jennifer H.; Knick, Victoria B.; Laudeman, Christopher P.; Luttrell, Deirdre K.; Mook, Robert A.; Nolte, Robert T.; Rudolph, Sharon K.; Szewczyk, Jerzy R.; Truesdale, Anne T.; Veal, James M.; Wang, Liping; Stafford, Jeffrey A.Journal of Medicinal Chemistry (2008), 51 (15), 4632-4640CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N4-(2,3-dimethyl-2H-indazol-6-yl)-N4-methyl-N2-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clin. development for renal-cell cancer and other solid tumors.
- 23Mulholland, P.; Batchelor, T. T.; Neyns, B. A phase III randomized study comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, with lomustine alone in recurrent glioblastoma patients Proc. ESMO Ann. Oncol. 2010, 21, LBA7
- 24Iwamoto, F. M.; Lamborn, K. R.; Robins, H. I.; Mehta, M. P.; Chang, S. M.; Butowski, N. A.; DeAngelis, L. M.; Abrey, L. E.; Zhang, W.-T.; Prados, M. D.; Fine, H. A. Phase II trial of pazopanib (GW786034), and oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06–02) Neuro Oncol. 2010, 12, 855– 861 DOI: 10.1093/neuonc/noq025[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvFSlt70%253D&md5=8b56b20e22512e58db6e4db2e9f13c6ePhase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02)Iwamoto, Fabio M.; Lamborn, Kathleen R.; Robins, H. Ian; Mehta, Minesh P.; Chang, Susan M.; Butowski, Nicholas A.; DeAngelis, Lisa M.; Abrey, Lauren E.; Zhang, Wei-Ting; Prados, Michael D.; Fine, Howard A.Neuro-Oncology (Cary, NC, United States) (2010), 12 (8), 855-861CODEN: NEURJR; ISSN:1522-8517. (Oxford University Press)The objective of this phase II single-arm study was to evaluate the efficacy and safety of pazopanib, a multi-targeted tyrosine kinase inhibitor, against vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor-α and -β, and c-Kit, in recurrent glioblastoma. Patients with ≤2 relapses and no prior anti-VEGF/VEGFR therapy were treated with pazopanib 800 mg daily on 4-wk cycles without planned interruptions. Brain magnetic resonance imaging and clin. reassessment were made every 8 wk. The primary endpoint was efficacy as measured by 6-mo progression-free survival (PFS6). Thirty-five GBM patients with a median age of 53 years and median Karnofsky performance scale of 90 were accrued. Grade 3/4 toxicities included leukopenia (n = 1), lymphopenia (n = 2), thrombocytopenia (n = 1), ALT elevation (n = 3), AST elevation (n = 1), CNS hemorrhage (n = 1), fatigue (n = 1), and thrombotic/embolic events (n = 3); 8 patients required dose redn. Two patients had a partial radiog. response by std. bidimensional measurements, whereas 9 patients (6 at the 8-wk point and 3 only within the first month of treatment) had decreased contrast enhancement, vasogenic edema, and mass effect but <50% redn. in tumor. The median PFS was 12 wk (95% confidence interval [CI]: 8-14 wk) and only 1 patient had a PFS time ≥6 mo (PFS6 = 3%). Thirty patients (86%) had died and median survival was 35 wk (95% CI: 24-47 wk). Pazopanib was reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR agents. Single-agent pazopanib did not prolong PFS in this patient population but showed in situ biol. activity as demonstrated by radiog. responses. ClinicalTrials.gov identifier: NCT00459381.
- 25Wang, T.; Agarwal, S.; Elmquist, W. F. Brain distribution of cediranib is limited by active efflux at the blood-brain barrier J. Pharmacol. Exp. Ther. 2012, 341, 386– 395 DOI: 10.1124/jpet.111.190488[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xmt1KntLo%253D&md5=e5c34f57afa96152ed0c612561eac08bBrain distribution of cediranib is limited by active efflux at the blood-brain barrierWang, Tianli; Agarwal, Sagar; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2012), 341 (2), 386-395CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Cediranib is an orally active tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor family. Because of its potent antiangiogenic and antitumor activities, cediranib has been evaluated for therapy in glioma, a primary brain tumor. This study investigated the influence of two important efflux transporters at the blood-brain barrier, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), on the delivery of cediranib to the central nervous system. In vitro studies indicated that cediranib is a dual substrate for both P-gp and Bcrp. It is noteworthy that in spite of the in vitro data the in vivo mouse disposition studies conclusively showed that P-gp was the dominant transporter restricting the brain distribution of cediranib. The brain-to-plasma partitioning (AUCbrain/AUCplasma, where AUC is area under the curve) and the steady-state brain-to-plasma concn. ratio of cediranib were approx. 20-fold higher in Mdr1a/b(-/-) and Mdr1a/b(-/-)Bcrp1(-/-) mice compared with wild-type and Bcrp1(-/-) mice. Moreover, there was no significant difference in brain distribution of cediranib between wild-type and Bcrp1(-/-) mice and between Mdr1a/b(-/-) and Mdr1a/b(-/-)Bcrp1(-/-) mice. These results show that, unlike other tyrosine kinase inhibitors that are dual substrates for P-gp and Bcrp, Bcrp does not restrict the distribution of cediranib across the blood-brain barrier. We also show that inhibition of P-gp using specific or nonspecific inhibitors resulted in significantly enhanced delivery of cediranib to the brain. Concurrent administration of cediranib with chem. modulators of efflux transporters can be used as a strategy to enhance delivery and thus efficacy of cediranib in the brain. These findings are clin. relevant to the efficacy of cediranib chemotherapy in glioma.
- 26Minocha, M.; Khurana, V.; Qin, B.; Pal, D.; Mitra, A. K. Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib Int. J. Pharm. 2012, 436, 127– 134 DOI: 10.1016/j.ijpharm.2012.05.038[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht12jsb%252FF&md5=12289c49082640d14eb72d464040df4fEnhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinibMinocha, Mukul; Khurana, Varun; Qin, Bin; Pal, Dhananjay; Mitra, Ashim K.International Journal of Pharmaceutics (Amsterdam, Netherlands) (2012), 436 (1-2), 127-134CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)Primary objective of this investigation was to delineate the differential impact of efflux transporters P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp1/Abcg2) on brain disposition and plasma pharmacokinetics of pazopanib. In addn., this research investigated whether inhibition of these efflux transporters with clin. relevant efflux modulators canertinib or erlotinib could be a viable strategy for improving pazopanib brain delivery. In vitro assays with MDCKII cell monolayers suggested that pazopanib is a high affinity substrate for Bcrp1 and a moderate substrate for P-gp. Co-incubation with specific transport inhibitors restored cell accumulation and completely abolished the directionality of pazopanib flux. Brain and plasma pharmacokinetic studies were conducted in FVB wild type mice in the absence and presence of specific transport inhibitors. Drug levels in plasma and brain were detd. using a validated high performance liq. chromatog. method using vandetanib as an internal std. In vivo studies indicated that specific inhibition of either P-gp (by zosuquidar or LY335979) or Bcrp1 (by Ko143) alone did not significantly alter pazopanib brain accumulation. However, dual P-gp/Bcrp1 inhibition by elacridar (GF120918), significantly enhanced pazopanib brain penetration by ∼5-fold without altering its plasma concns. Thus, even though Bcrp1 showed higher affinity towards pazopanib in vitro, in vivo at the mouse BBB both P-gp and Bcrp1 act in concert to limit brain accumulation of pazopanib. Furthermore, erlotinib and canertinib as clin. relevant efflux modulators efficiently abrogated directionality in pazopanib efflux in vitro and their co-administration resulted in 2-2.5-fold increase in pazopanib brain accumulation in vivo. Further pre-clin. and clin. investigations are warranted as erlotinib or canertinib may have a synergistic pharmacol. effect in addn. to their primary role of pazopanib efflux modulation as a combination regimen for the treatment of recurrent brain tumors.
- 27Atkins, M.; Jones, C. A.; Kirkpatrick, P. Sunitinib maleate Nat. Rev. Drug Discovery 2006, 5, 279– 280 DOI: 10.1038/nrd2012
- 28Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R. A.; Schwartz, B.; Simantov, R.; Kelley, S. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer Nat. Rev. Drug Discovery 2006, 5, 835– 844 DOI: 10.1038/nrd2130[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVajsbbM&md5=490d4995170f3a7270ae9bbdd24b12e5Discovery and development of sorafenib: a multikinase inhibitor for treating cancerWilhelm, Scott; Carter, Christopher; Lynch, Mark; Lowinger, Timothy; Dumas, Jacques; Smith, Roger A.; Schwartz, Brian; Simantov, Ronit; Kelley, SusanNature Reviews Drug Discovery (2006), 5 (10), 835-844CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Since the mol. revolution of the 1980s, knowledge of the etiol. of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, the authors describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumor signaling and the tumor vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) - from initial screening for a lead compd. to FDA approval for the treatment of advanced renal cell carcinoma in Dec. 2005 - was completed in just 11 years, with approval being received ∼5 years after the initiation of the first Phase I trial.
- 29Roth, G. J.; Binder, R.; Colbatzky, F.; Dallinger, C.; Schlenker-Herceq, R.; Hilberg, F.; Wollin, S. L.; Kaiser, R. Nintedanib: from discovery to the clinic J. Med. Chem. 2015, 58, 1053– 1063 DOI: 10.1021/jm501562a[ACS Full Text], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVegurnO&md5=dd1bc3c81b83b21cfb9b0d3da7f7b55dNintedanib: From Discovery to the ClinicRoth, Gerald J.; Binder, Rudolf; Colbatzky, Florian; Dallinger, Claudia; Schlenker-Herceg, Rozsa; Hilberg, Frank; Wollin, Stefan-Lutz; Kaiser, RolfJournal of Medicinal Chemistry (2015), 58 (3), 1053-1063CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Nintedanib (BIBF1120) is a potent, oral, small-mol. tyrosine kinase inhibitor, also known as a triple angiokinase inhibitor, inhibiting three major signaling pathways involved in angiogenesis. Nintedanib targets proangiogenic and pro-fibrotic pathways mediated by the VEGFR family, the fibroblast growth factor receptor (FGFR) family, the platelet-derived growth factor receptor (PDGFR) family, as well as Src and Flt-3 kinases. The compd. was identified during a lead optimization program for small-mol. inhibitors of angiogenesis and has since undergone extensive clin. investigation for the treatment of various solid tumors, and in patients with the debilitating lung disease idiopathic pulmonary fibrosis (IPF). Recent clin. evidence from phase III studies has shown that nintedanib has significant efficacy in the treatment of NSCLC, ovarian cancer, and IPF. This review article provides a comprehensive summary of the preclin. and clin. research and development of nintedanib from the initial drug discovery process to the latest available clin. trial data.
- 30Nakamura, K.; Taguchi, E.; Miura, T.; Yamamoto, A.; Takahashi, K.; Bichat, F.; Guilbaud, N.; Hasegawa, K.; Kubo, K.; Fujiwara, Y.; Suzuki, R.; Kubo, K.; Shibuya, M.; Isae, T. KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties Cancer Res. 2006, 66, 9134– 9142 DOI: 10.1158/0008-5472.CAN-05-4290
- 31Renhowe, P. A.; Pecchi, S.; Shafer, C. M.; Machajewski, T. D.; Jazan, E. M.; Taylor, C.; Antonios-McCrea, W.; McBride, C. M.; Frazier, K.; Wiesmann, M.; Lapointe, G. R.; Feucht, P. H.; Warne, R. L.; Heise, C. C.; Menezes, D.; Aardalen, K.; Ye, H.; He, M.; Le, V.; Vora, J.; Jansen, J. M.; Wernette-Hammond, M. E.; Harris, A. L. Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors J. Med. Chem. 2009, 52, 278– 292 DOI: 10.1021/jm800790t[ACS Full Text], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnt1Sl&md5=f20f564bb7dacb5a450a29dae9e04b50Design, Structure-Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase InhibitorsRenhowe, Paul A.; Pecchi, Sabina; Shafer, Cynthia M.; Machajewski, Timothy D.; Jazan, Elisa M.; Taylor, Clarke; Antonios-McCrea, William; McBride, Christopher M.; Frazier, Kelly; Wiesmann, Marion; Lapointe, Gena R.; Feucht, Paul H.; Warne, Robert L.; Heise, Carla C.; Menezes, Daniel; Aardalen, Kimberly; Ye, Helen; He, Molly; Le, Vincent; Vora, Jayesh; Jansen, Johanna M.; Wernette-Hammond, Mary Ellen; Harris, Alex L.Journal of Medicinal Chemistry (2009), 52 (2), 278-292CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncol. research over the last several years. Many potent small mol. inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compds. that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clin. efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogs as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compds. in this class, such as TKI258 (I), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRβ with IC50 values <0.1 μM. On the basis of its favorable in vitro and in vivo properties, compd. I was selected for clin. evaluation and is currently in phase I clin. trials.
- 32(a) Balana, C.; Gil, M. J.; Reynes, G.; Capellades, J.; Ribalta, T.; Gallego, O.; Segura, P. P.; Verger, E. A phase II multicentric study of sunitinib administered as upfront therapy in glioblastoma: a study by the GEINO group J. Clin. Oncol. 2012, 30, 2045(b) Kreisl, T. N.; Smith, P.; Sul, J.; Salgado, C.; Iwamoto, F. M.; Shih, J. H.; Fine, H. A. Continuous daily sunitinib for recurrent glioblastoma J. Neuro-Oncol. 2013, 111, 41– 48 DOI: 10.1007/s11060-012-0988-z[Crossref], [PubMed], [CAS], Google Scholar32bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvFSgtLnN&md5=74c5a15570b521164f7813043d4f3ee8Continuous daily sunitinib for recurrent glioblastomaKreisl, Teri Nguyen; Smith, Perry; Sul, Joohee; Salgado, Carlos; Iwamoto, Fabio M.; Shih, Joanna H.; Fine, Howard A.Journal of Neuro-Oncology (2013), 111 (1), 41-48CODEN: JNODD2; ISSN:0167-594X. (Springer)Bevacizumab (BEV) has become a mainstay of treating recurrent glioblastoma, but eventual tumor resistance is expected. Targeting multiple growth-assocd. signaling pathways may result in more effective treatment than targeting VEGF alone. Patients with recurrent glioblastoma were stratified by prior BEV exposure and treated with sunitinib 37.5 mg daily in this phase II study. Response evaluations were performed at baseline and at the end of every 4 wk cycle. Six-month progression-free survival (PFS6) was the primary endpoint for both arms of the study. Secondary endpoints included health related quality of life measures and FDG-PET correlatives with patient outcomes. Sixty-three patients were accrued to this study; thirty-two were BEV-naive, 31 were BEV-resistant. PFS6 was 10.4 % [95 % CI 3.2-33.8] in the BEV-naive cohort and 0 % in the BEV-resistant cohort. Median overall survival was 9.4 mo [95 % CI 6.15-21.90] in the BEV-naive cohort and 4.37 mo [95 % CI 3.02-6.21] in the BEV-resistant cohort. 3/29 patients (10 %) of the BEV-naive, and 0/27 BEV-resistant patients achieved radiog. response. Thrombocytopenia, leukopenia, and neutropenia were the most common drug-assocd. adverse events and occurred with higher frequency than expected. Sunitinib treatment in BEV-naive patients did not appear to affect outcomes with subsequent BEV therapy. Continuous daily sunitinib did not prolong progression-free survival in BEV-naive nor BEV-resistant patients with recurrent glioblastoma.(c) Reardon, D. A.; Vredenburgh, J. J.; Coan, A.; Desjardins, A.; Peters, K. B.; Gururangan, S.; Sathornsumetee, S.; Rich, J. N.; Herndon, J. E.; Friedman, H. S. Phase I study of sunitinib and irinotecan for patients with recurrent malignant glioma J. Neuro-Oncol. 2011, 105, 621– 627 DOI: 10.1007/s11060-011-0631-4[Crossref], [PubMed], [CAS], Google Scholar32chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVyrtLfK&md5=a0f07732c407a80b4f742b5b1da09622Phase I study of sunitinib and irinotecan for patients with recurrent malignant gliomaReardon, David A.; Vredenburgh, James J.; Coan, April; Desjardins, Annick; Peters, Katherine B.; Gururangan, Sridharan; Sathornsumetee, Sith; Rich, Jeremy N.; Herndon, James E.; Friedman, Henry S.Journal of Neuro-Oncology (2011), 105 (3), 621-627CODEN: JNODD2; ISSN:0167-594X. (Springer)We detd. the max. tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, sunitinib, when administered with irinotecan among recurrent malignant glioma (MG) patients. For each 42-day cycle, sunitinib was administered once a day for four consecutive weeks followed by a 2 wk rest. Irinotecan was administered i.v. every other week. Each agent was alternatively escalated among cohorts of 3-6 patients enrolled at each dose level. Patients on CYP3A-inducing anti-epileptic drugs were not eligible. Twenty-five patients with recurrent MG were enrolled, including 15 (60%) with glioblastoma (GBM) and 10 (40%) with grade 3 MG. Five patients progressed previously on bevacizumab and two had received prior VEGFR tyrosine kinase inhibitor therapy. The MTD was 50 mg of sunitinib combined with 75 mg/m2 of irinotecan. DLT were primarily hematol. and included grade 4 neutropenia in 3 patients and one patient with grade 4 thrombocytopenia. Non-hematol. DLT included grade 3 mucositis (n = 1) and grade 3 dehydration (n = 1). Progression-free survival (PFS)-6 was 24% and only one patient achieved a radiog. response. The combination of sunitinib and irinotecan was assocd. with moderate toxicity and limited anti-tumor activity. Further studies with this regimen using the dosing schedules evaluated in this study are not warranted.
- 33(a) Lee, E. Q.; Kuhn, J.; Lamborn, K. R.; Abrey, L.; DeAngelis, L. M.; Lieberman, F.; Robins, H. I.; Chang, S. M.; Yung, W. K. A.; Drappatz, J.; Mehta, M. P.; Levin, V. A.; Aldape, K.; Dancey, J. E.; Wright, J. J.; Prados, M. D.; Cloughesy, T. F.; Gilbert, M. R.; Wen, P. Y. Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02 Neuro-Oncology 2012, 14, 1511– 1518 DOI: 10.1093/neuonc/nos264(b) Hainsworth, J. D.; Ervin, T.; Friedman, E.; Priego, V.; Murphy, P. B.; Clark, B. L.; Lamar, R. E. Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first-line treatment of patients with glioblastoma multiforme Cancer 2010, 116, 3663– 3669 DOI: 10.1002/cncr.25275
- 34Muhic, A.; Poulsen, H. S.; Sorensen, M.; Grunnet, K.; Lassen, U. Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme J. Neuro-Oncol. 2013, 111, 205– 212 DOI: 10.1007/s11060-012-1009-y[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpt1Kiuw%253D%253D&md5=e380c9967f338d6cfd73d383d5132393Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiformeMuhic, Aida; Poulsen, Hans Skovgaard; Sorensen, Morten; Grunnet, Kirsten; Lassen, UlrikJournal of Neuro-Oncology (2013), 111 (2), 205-212CODEN: JNODD2; ISSN:0167-594X. (Springer)Nintedanib (BIBF 1120) is a small, orally available, triple angiokinase inhibitor in phase III development (various indications) that targets VEGFR 1-3, FGFR 1-3, and PDGFR-α/β. This open-label, uncontrolled, phase II study assessed the efficacy and safety of nintedanib in patients with recurrent glioblastoma multiforme (GBM) who had previously failed radiotherapy plus temozolomide as first-line therapy (STUPP), or the same regimen with subsequent bevacizumab-based therapy as second-line treatment (BEV). Patients with a performance status of 0-1, histol. proven GBM, and measurable disease (by RANO) were enrolled. Nintedanib was given orally at a dose of 200 mg twice daily (bid), with magnetic resonance imaging undertaken every 8 wk. The primary endpoint was objective response rate. The study was stopped prematurely following a preplanned futility anal. after inclusion of 13 patients in the STUPP arm and 12 in the BEV arm. Best response was stable disease (SD) in three patients (12 %); all other patients progressed within the first four 28-day cycles. One patient in the BEV arm has had SD for 17+ months. Median progression-free survival was 1 mo and median overall survival was 6 mo. Nintedanib had an acceptable safety profile, with no CTCAE grade 3-4 adverse events. Common adverse events were CTCAE grade 1-2 fatigue, loss of appetite, diarrhea, and nausea. Single-agent nintedanib (200 mg bid) demonstrated limited, but clin. non-relevant antitumor activity in patients with recurrent GBM who had failed 1-2 prior lines of therapy.
- 35Cai, X.; Chandra, V.; Ou, Y.; Emblem, K. E.; Muzikansky, A.; Evans, J.; Kalpathy-Cramer, J.; Dietrich, J.; Chi, A. S.; Wen, P. Y.; Rosen, B. R.; Batchelor, T.; Gerstner, E. R.; Martinos, A. A. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma J. Clin. Oncol. 2015, 33 (Suppl.) 2025
- 36Ahluwalia, M. S.; Papadantonakis, N.; Venur, V. A.; Schilero, C.; Peereboom, D. M.; Stevens, G.; Rosenfeld, S.; Vogelbaum, M. A.; Elson, P.; Nixon, A. B.; McCrae, K. Phase II trial of dovitinib in recurrent glioblastoma J. Clin. Oncol. 2015, 33 (Suppl.) 2050
- 37(a) Oberoi, R. K.; Mittapalli, R. K.; Fisher, J.; Elmquist, W. F. Sunitinib LC-MS/MS assay in mouse plasma and brain tissue: application in CNS distribution studies Chromatographia 2013, 76, 1657– 1665 DOI: 10.1007/s10337-013-2528-1(b) Tang, S. C.; Lagas, J. S.; Lankheet, N. A. G.; Poller, B.; Hillebrand, M. J.; Rosing, H.; Bejinen, J. H.; Schinkel, A. H. Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration Int. J. Cancer 2012, 130, 223– 233 DOI: 10.1002/ijc.26000[Crossref], [PubMed], [CAS], Google Scholar37bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlOmsrjP&md5=47fee810fd84296c9b1598fd8e80acf7Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministrationTang, Seng Chuan; Lagas, Jurjen S.; Lankheet, Nienke A. G.; Poller, Birk; Hillebrand, Michel J.; Rosing, Hilde; Beijnen, Jos H.; Schinkel, Alfred H.International Journal of Cancer (2012), 130 (1), 223-233CODEN: IJCNAW; ISSN:0020-7136. (John Wiley & Sons, Inc.)Sunitinib is an orally active, multitargeted tyrosine kinase inhibitor which has been used for the treatment of metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. We aimed to investigate the in vivo roles of the ATP-binding cassette drug efflux transporters ABCB1 and ABCG2 in plasma pharmacokinetics and brain accumulation of oral sunitinib, and the feasibility of improving sunitinib kinetics using oral coadministration of the dual ABCB1/ABCG2 inhibitor elacridar. We used in vitro transport assays and Abcb1a/1b-/-, Abcg2-/- and Abcb1a/1b/Abcg2-/- mice to study the roles of ABCB1 and ABCG2 in sunitinib disposition. In vitro, sunitinib was a good substrate of murine (mu)ABCG2 and a moderate substrate of human (hu)ABCB1 and huABCG2. In vivo, the systemic exposure of sunitinib after oral dosing (10 mg kg-1) was unchanged when muABCB1 and/or muABCG2 were absent. Brain accumulation of sunitinib was markedly (23-fold) increased in Abcb1a/b/Abcg2-/- mice, but only slightly (2.3-fold) in Abcb1a/b-/- mice, and not in Abcg2-/- mice. Importantly, a clin. realistic coadministration of oral elacridar and oral sunitinib to wild-type mice resulted in markedly increased sunitinib brain accumulation, equaling levels in Abcb1a/1b/Abcg2-/- mice. This indicates complete inhibition of the blood-brain barrier (BBB) transporters. High-dose i.v. sunitinib could sat. BBB muABCG2, but not muABCB1A, illustrating a dose-dependent relative impact of the BBB transporters. Brain accumulation of sunitinib is effectively restricted by both muABCB1 and muABCG2 activity. Complete inhibition of both transporters, leading to markedly increased brain accumulation of sunitinib, is feasible and safe with a clin. realistic oral elacridar/sunitinib coadministration.
- 38(a) Lagas, J. S.; van Waterschoot, R. A. B.; Sparidans, R. W.; Wagenaar, E.; Beijnen, J. H.; Schinkel, A. H. Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation Mol. Cancer Ther. 2010, 9, 319– 326 DOI: 10.1158/1535-7163.MCT-09-0663[Crossref], [PubMed], [CAS], Google Scholar38ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhslektLo%253D&md5=f7d2e4cb7f706f63320bddc603103462Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain AccumulationLagas, Jurjen S.; van Waterschoot, Robert A. B.; Sparidans, Rolf W.; Wagenaar, Els; Beijnen, Jos H.; Schinkel, Alfred H.Molecular Cancer Therapeutics (2010), 9 (2), 319-326CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Sorafenib is a second-generation, orally active multikinase inhibitor that is approved for the treatment of patients with advanced renal cell carcinoma and patients with unresectable hepatocellular carcinoma. The authors studied active transport of sorafenib in MDCK-II cells expressing human P-glycoprotein (P-gp/ABCB1) or ABCG2 (breast cancer resistance protein) or murine Abcg2. Sorafenib was moderately transported by P-gp and more efficiently by ABCG2 and Abcg2. Because sorafenib is taken orally, the authors orally administered sorafenib to wild-type, Abcb1a/1b-/-, Abcg2-/-, and Abcb1a/1b;Abcg2-/- mice, completely lacking functional Abcb1a/1b, Abcg2, or both, resp., and the authors studied plasma pharmacokinetics and brain accumulation. The systemic exposure on oral administration was not different among all strains. However, brain accumulation was 4.3-fold increased in Abcg2-/- mice and 9.3-fold increased in Abcb1a/1b;Abcg2-/- mice. Moreover, when wild-type mice were treated with sorafenib in combination with the dual P-gp and ABCG2 inhibitor elacridar, brain accumulation was similar to that obsd. for Abcb1a/1b;Abcg2-/- mice. These results show that the brain accumulation of sorafenib is primarily restricted by ABCG2. This contrasts with previous studies using shared ABCG2 and P-gp substrates, which all suggested that P-gp dominates at the blood-brain barrier, and that an effect of ABCG2 is only evident when both transporters are absent. Interestingly, for sorafenib, it is the other way around, i.e., ABCG2, and not P-gp, plays the dominant role in restricting its brain accumulation. Clin., the authors' findings may be relevant for the treatment of renal cell carcinoma patients with central nervous system relapses, as a dual ABCG2 and P-gp inhibitor might improve the central nervous system entry and thereby the therapeutic efficacy of sorafenib. Mol Cancer Ther; 9(2); 319-26.(b) Agarwal, S.; Sane, R.; Ohlfest, J. R.; Elmquist, W. F. The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain J. Pharmacol. Exp. Ther. 2011, 336, 223– 233 DOI: 10.1124/jpet.110.175034[Crossref], [PubMed], [CAS], Google Scholar38bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXls1eqtg%253D%253D&md5=9d8057bda22f1dc0ab81aea9fb7906a0The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brainAgarwal, Sagar; Sane, Ramola; Ohlfest, John R.; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2011), 336 (1), 223-233CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)ATP-binding cassette transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) have been shown to work in concert to restrict brain penetration of several tyrosine kinase inhibitors. It has been reported that P-gp is dominant in limiting transport of many dual P-gp/BCRP substrates across the blood-brain barrier (BBB). This study investigated the influence of P-gp and BCRP on the central nervous system (CNS) penetration of sorafenib, a multitargeted tyrosine kinase inhibitor currently being evaluated in clin. trials for glioma. In vitro studies showed that BCRP has a high affinity for sorafenib. Sorafenib inhibited P-gp, but did not seem to be a P-gp substrate in vitro. CNS distribution studies showed that transport of sorafenib to the brain was restricted because of active efflux at the BBB. The brain-to-plasma equil.-distribution coeff. (area under the concn.-time profiles for plasma/area under the concn.-time profiles for brain) was 0.06 in wild-type mice. Steady-state brain-to-plasma concn. ratio of sorafenib was approx. 0.36 ± 0.056 in the Bcrp1(-/-) mice, 0.11 ± 0.021 in the Mdr1a/b(-/-) mice, and 0.91 ± 0.29 in the Mdr1a/b(-/-)Bcrp1(-/-) mice compared with 0.094 ± 0.007 in the wild-type mice. Sorafenib brain-to-plasma ratios increased on coadministration of the dual P-gp/BCRP inhibitor elacridar such that the ratio in wild-type mice (0.76 ± 0.24), Bcrp1(-/-) mice (1.03 ± 0.33), Mdr1a/b(-/-) mice (1.3 ± 0.29), and Mdr1a/b(-/-)Bcrp1(-/-) mice (0.73 ± 0.35) were not significantly different. This study shows that BCRP and P-gp together restrict the brain distribution of sorafenib with BCRP playing a dominant role in the efflux of sorafenib at the BBB. These findings are clin. relevant to chemotherapy in glioma if restricted drug delivery to the invasive tumor cells results in decreased efficacy.(c) Asakawa, C.; Ogawa, M.; Kumata, K.; Fujinaga, M.; Kato, K.; Yamasaki, T.; Yui, J.; Kawamura, K.; Hatori, A.; Fukumura, T.; Zhang, M.-R. [11C]Sorafenib: radiosynthesis and preliminary PET study of brain uptake in P-gp/Bcrp knockout mice Bioorg. Med. Chem. Lett. 2011, 21, 2220– 2223 DOI: 10.1016/j.bmcl.2011.03.002
- 39Hussar, D. A.; Jeon, M. M. Naloxegol oxalate, pirfenidone, and nintedanib J. Am. Pharm. Assoc. 2015, 55, 461– 463 DOI: 10.1331/JAPhA.2015.15523
- 40Helgason, H. H.; Mallo, H. A.; Droogendijk, H.; Haanen, J. G.; van der Veldt, A. A. M.; van den Eertwegh, A. J.; Boven, E. Brain metastases in patients with renal cell cancer receiving new targeted treatment J. Clin. Oncol. 2008, 26, 152– 154 DOI: 10.1200/JCO.2007.13.5814[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c%252Fgt1ertg%253D%253D&md5=709cd92719a0dcb5849966d939d795b0Brain metastases in patients with renal cell cancer receiving new targeted treatmentHelgason Helgi H; Mallo Henk A; Droogendijk Helga; Haanen John G; van der Veldt Astrid A M; van den Eertwegh Alfonsus J; Boven EpieJournal of clinical oncology : official journal of the American Society of Clinical Oncology (2008), 26 (1), 152-4 ISSN:.There is no expanded citation for this reference.
- 41Wilhelm, S. M.; Dumas, J.; Adnane, L.; Lynch, M.; Carter, C. A.; Schutz, G.; Thierauch, K. H.; Zopf, D. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity Int. J. Cancer 2011, 129, 245– 255 DOI: 10.1002/ijc.25864[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltFGlu7c%253D&md5=13eee29ef1f1f03fd1ed311ea613f566Regorafenib (BAY 73-4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activityWilhelm, Scott M.; Dumas, Jacques; Adnane, Lila; Lynch, Mark; Carter, Christopher A.; Schuetz, Gunnar; Thierauch, Karl-Heinz; Zopf, DieterInternational Journal of Cancer (2011), 129 (1), 245-255CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)Angiogenesis, a crit. driver of tumor development, is controlled by interconnected signaling pathways. Vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with Ig and epidermal growth factor homol. domain 2 play crucial roles in the biol. of normal and tumor vasculature. Regorafenib (BAY 73-4506), a novel oral multikinase inhibitor, potently inhibits these endothelial cell kinases in biochem. and cellular kinase phosphorylation assays. Furthermore, regorafenib inhibits addnl. angiogenic kinases (VEGFR1/3, platelet-derived growth factor receptor-β and fibroblast growth factor receptor 1) and the mutant oncogenic kinases KIT, RET and B-RAF. The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast-enhanced magnetic resonance imaging. Regorafenib administered once orally at 10 mg/kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts. In a daily (qd)×4 dosing study, the pharmacodynamic effects persisted for 48 h after the last dosing and correlated with tumor growth inhibition (TGI). A significant redn. in tumor microvessel area was obsd. in a human colorectal xenograft after qd×5 dosing at 10 and 30 mg/kg. Regorafenib exhibited potent dose-dependent TGI in various preclin. human xenograft models in mice, with tumor shrinkages obsd. in breast MDA-MB-231 and renal 786-O carcinoma models. Pharmacodynamic analyses of the breast model revealed strong redn. in staining of proliferation marker Ki-67 and phosphorylated extracellular regulated kinases 1/2. These data demonstrate that regorafenib is a well-tolerated, orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies.
- 42EU Clinical Trials Register. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-003722-41 (accessed June 9, 2016) .
- 43Kort, A.; Durmus, S.; Sparidans, R. W.; Wagenaar, E.; Beijnen, J. H.; Schinkel, A. H. Brain and testis accumulation of regorafenib is restricted by breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) Pharm. Res. 2015, 32, 2205– 2216 DOI: 10.1007/s11095-014-1609-7
- 44Yang, J. J.; Milton, M. N.; Liao, M.; Liu, N.; Wu, J. T.; Gan, L.; Balani, S. K.; Lee, F. W.; Prakash, S.; Xia, C. Q. P-glycloprotein and breast cancer resistance protein affect disposition of tandutinib, a tyrosine kinase inhibitor Drug Metab. Lett. 2010, 4, 202– 212 DOI: 10.2174/187231210792928279[Crossref], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFCit73I&md5=33eda66652a724416094b4d1823ec424P-glycoprotein and breast cancer resistance protein affect disposition of tandutinib, a tyrosine kinase inhibitorYang, Johnny J.; Milton, Mark N.; Yu, Shaoxia; Liao, Mingxiang; Liu, Ning; Wu, Jing-Tao; Gan, Liang-Shang; Balani, Suresh K.; Lee, Frank W.; Prakash, Shimoga; Xia, Cindy Q.Drug Metabolism Letters (2010), 4 (4), 202-212CODEN: DMLRBM; ISSN:1872-3128. (Bentham Science Publishers Ltd.)Tandutinib is a tyrosine kinase inhibitor under investigation for the treatment of solid and hematol. tumors. We evaluated efflux transporter substrate specificity of tandutinib in Caco-2 cells, and the role of efflux transporters in the disposition of tandutinib in rats and efflux transporter knock-out mice. These studies demonstrated that tandutinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in Caco-2 cells. In rats, administration of GF120918, before treatment with tandutinib orally resulted in approx. a seven-fold increase in the mean plasma area under the concn.-vs.-time curve (AUC) compared to the vehicle control group. In mice, after i.v. administration of tandutinib, the mean plasma AUC values in the Bcrp1(-/-) mice and Mdr1a/b(-/-) mice was 1.53- and 1.20-fold greater than that of the wild type (WT) mice, resp. After oral administration, the drug exposure in Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)/Bcrp1(-/-) mice was higher than in the WT mice. The brain to plasma exposure ratio (B/P) of tandutinib in Mdr1a/b(-/-) mice increased by 2- to 3-fold over that in the WT mice. There was a 13-fold increase in B/P in Mdr1a/b(-/-)/Bcrp1(-/-) mice. This finding illustrates that P-gp and Bcrp play a role in oral absorption, systemic clearance, and brain penetration of tandutinib in the rodents. P-gp affected oral absorption and brain penetration of tandutinib to a greater extent than Bcrp, but Bcrp contribution to systemic clearance of tandutinib was greater than P-gp. Thus, co-administration of efflux pump inhibitors may be a useful strategy to enhance tandutinib absorption and brain penetration clin.
- 45Supko, J. G.; Grossman, S. A.; Peereboom, D. M.; Chowdhary, S.; Lesser, G. J.; Nabors, L. B.; Mikkelsen, T.; Desideri, S.; Batchelor, T. T. Feasibility and phase I trial of tandutinib in patients with recurrent glioblastoma J. Clin. Oncol. 2009, 27 (15s) 2039
- 46Lu, L.; Saha, D.; Martuza, R. L.; Rabkin, S. D.; Wakimoto, H. Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastoma J. Neuro-Oncol. 2015, 121, 91– 100 DOI: 10.1007/s11060-014-1612-1[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFGhu7zK&md5=0d0dfdb9ee7a3adce51badb64a322448Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastomaLu, Lei; Saha, Dipongkor; Martuza, Robert L.; Rabkin, Samuel D.; Wakimoto, HiroakiJournal of Neuro-Oncology (2015), 121 (1), 91-100CODEN: JNODD2; ISSN:0167-594X. (Springer)Anti-angiogenic therapy is a promising therapeutic strategy for the highly vascular and malignant brain tumor, glioblastoma (GBM), although current clin. trials have failed to demonstrate an extension in overall survival. The small mol. tyrosine kinase inhibitor axitinib that targets vascular endothelial growth factor receptor, potently inhibits angiogenesis and has single-agent clin. activity in non-small cell lung, thyroid, and advanced renal cell cancer. Here we show that axitinib exerts direct cytotoxic activity against a no. of patient-derived GBM stem cell (GSCs) and an endothelial cell line, and inhibits endothelial tube formation in vitro. Axitinib treatment of mice bearing hypervascular intracranial tumors generated from human U87 glioma cells, MGG4 GSCs and mouse 005 GSCs significantly extended survival that was assocd. with decreases in tumor-assocd. vascularity. We thus show for the first time the anti-angiogenic effect and survival prolongation provided by systemic single agent treatment with axitinib in preclin. orthotopic GBM models including clin. relevant GSC models. These results support further investigation of axitinib as an anti-angiogenic agent for GBM.
- 47Zakharia, Y.; Zakharia, K.; Rixe, O. Axitinib: from preclinical development to future clinical perspectives in renal cell carcinoma Expert Opin. Drug Discovery 2015, 10, 925– 935 DOI: 10.1517/17460441.2015.1045411
- 48Neyns, B.; Duerinck, J.; Du Four, S.; Bouttens, F.; Verschaeve, V.; Everaert, H.; Van Binst, A. Randomized phase II study of axitinib versus standard of care in patients with recurrent glioblastoma J. Clin. Oncol. 2014, 32 (Suppl.) 2018
- 49Poller, B.; Iusuf, D.; Sparidans, R. W.; Wagenaar, E.; Beijnen, J. H.; Schinkel, A. H. Differential impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on axitinib brain accumulation and oral plasma pharmacokinetics Drug Metab. Dispos. 2011, 39, 729– 735 DOI: 10.1124/dmd.110.037317
- 50Sim, M. W.; Cohen, M. S. The discovery and development of vandetanib for the treatment of thyroid cancer Expert Opin. Drug Discovery 2014, 9, 105– 114 DOI: 10.1517/17460441.2014.866942
- 51Matsui, J.; Yamamoto, Y.; Funahashi, Y.; Tsuruoka, A.; Watanabe, T.; Wakabayashi, T.; Uenaka, T.; Asada, M. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition Int. J. Cancer 2008, 122, 664– 671 DOI: 10.1002/ijc.23131[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2sjhvVGnsA%253D%253D&md5=cfa467e773fd98d6f95b0dded62d31efE7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibitionMatsui Junji; Yamamoto Yuji; Funahashi Yasuhiro; Tsuruoka Akihiko; Watanabe Tatsuo; Wakabayashi Toshiaki; Uenaka Toshimitsu; Asada MakotoInternational journal of cancer (2008), 122 (3), 664-71 ISSN:.E7080 is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. In this study, we show the inhibitory activity of E7080 against SCF-induced angiogenesis in vitro and tumor growth of SCF-producing human small cell lung carcinoma H146 cells in vivo. E7080 inhibits SCF-driven tube formation of HUVEC, which express SCF receptor, KIT at the IC(50) value of 5.2 nM and it was almost identical for VEGF-driven one (IC(50) = 5.1 nM). To assess the role of SCF/KIT signaling in tumor angiogenesis, we evaluated the effect of imatinib, a selective KIT kinase inhibitor, on tumor growth of H146 cells in nude mice. Imatinib did not show the potent antitumor activity in vitro (IC(50) = 2,200 nM), because H146 cells did not express KIT. However, oral administration of imatinib at 160 mg/kg clearly slowed tumor growth of H146 cells in nude mice, accompanied by decreased microvessel density. Oral administration of E7080 inhibited tumor growth of H146 cells at doses of 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg. While anti-VEGF antibody also slowed tumor growth, it did not cause tumor regression. These results indicate that KIT signaling has a role in tumor angiogenesis of SCF-producing H146 cells, and E7080 causes regression of H146 tumors as a result of antiangiogenic activity mediated by inhibition of both KIT and VEGF receptor signaling. E7080 may provide therapeutic benefits in the treatment of SCF-producing tumors.
- 52(a) Drappatz, J.; Norden, A. D.; Wong, E. T.; Doherty, L. M.; LaFrankie, D. C.; Ciampa, A.; Kesari, S.; Sceppa, C.; Gerard, M.; Phan, P.; Schiff, D.; Batchelor, T. T.; Ligon, K. L.; Young, G.; Muzikansky, A.; Weiss, S. E.; Wen, P. Y. Phase I study of vandetanib with radiotherapy and temozolomide for newly diagnosed glioblastoma Int. J. Radiat. Oncol., Biol., Phys. 2010, 78, 85– 90 DOI: 10.1016/j.ijrobp.2009.07.1741[Crossref], [PubMed], [CAS], Google Scholar52ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVaqtr7E&md5=c0f43c60f1714769257fce187b91de3fPhase I Study of Vandetanib With Radiotherapy and Temozolomide for Newly Diagnosed GlioblastomaDrappatz, Jan; Norden, Andrew D.; Wong, Eric T.; Doherty, Lisa M.; LaFrankie, Debra C.; Ciampa, Abigail; Kesari, Santosh; Sceppa, Christine; Gerard, Mary; Phan, Phuong; Schiff, David; Batchelor, Tracy T.; Ligon, Keith L.; Young, Geoffrey; Muzikansky, Alona; Weiss, Stephanie E.; Wen, Patrick Y.International Journal of Radiation Oncology, Biology, Physics (2010), 78 (1), 85-90CODEN: IOBPD3; ISSN:0360-3016. (Elsevier Inc.)Purpose: Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addn., epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ). Methods and Materials: A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvant TMZ, using a std. "3 + 3" dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 wk of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of ≥60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs. Results: Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 wk, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities obsd., establishing this dose as the maximal tolerated dose combined with TMZ and RT. Conclusion: Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway.(b) Chheda, M. G.; Wen, P. Y.; Hochberg, F. H.; Chi, A. S.; Drappatz, J.; Eichler, A. F.; Yang, D.; Beroukhim, R.; Norden, A. D.; Gerstner, E. R.; Betensky, R. A.; Batchelor, T. T. Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort study J. Neuro-Oncol. 2015, 121, 627– 634 DOI: 10.1007/s11060-014-1680-2[Crossref], [PubMed], [CAS], Google Scholar52bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFOku7fM&md5=45c84a46e3700560618c06bd4ba6a330Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort studyChheda, Milan G.; Wen, Patrick Y.; Hochberg, Fred H.; Chi, Andrew S.; Drappatz, Jan; Eichler, April F.; Yang, Daniel; Beroukhim, Rameen; Norden, Andrew D.; Gerstner, Elizabeth R.; Betensky, Rebecca A.; Batchelor, Tracy T.Journal of Neuro-Oncology (2015), 121 (3), 627-634CODEN: JNODD2; ISSN:0167-594X. (Springer)Targeting specific mol. alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to det. the max. tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, resp. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 mo (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule.(c) Kreisl, T. N.; McNeill, K. A.; Sul, J.; Iwamoto, F. M.; Shih, J.; Fine, H. A. A phase I/II trial of vandetanib for patients with recurrent malignant glioma Neuro-Oncology 2012, 14, 1519– 1526 DOI: 10.1093/neuonc/nos265(d) Subbiah, V.; Berry, J.; Roxas, M.; Guha-Thakurta, N.; Subbiah, I. M.; Ali, S. M.; McMahon, C.; Miller, V.; Cascone, T.; Pai, S.; Tang, Z.; Heymach, J. V. Systemic and CNS activity of the RET inhibitor vandetanib combined with the mTOR inhibitor everolimus in KIF5B-RET re-arranged non-small cell lung cancer with brain metastases Lung Cancer 2015, 89, 76– 79 DOI: 10.1016/j.lungcan.2015.04.004[Crossref], [PubMed], [CAS], Google Scholar52dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfkvVemsw%253D%253D&md5=3f397ffcdf953e5121326786659d730bSystemic and CNS activity of the RET inhibitor vandetanib combined with the mTOR inhibitor everolimus in KIF5B-RET re-arranged non-small cell lung cancer with brain metastasesSubbiah Vivek; Berry Jenny; Roxas Michael; Guha-Thakurta Nandita; Subbiah Ishwaria Mohan; Cascone Tina; Pai Shobha; Tang Zhenya; Heymach John V; Ali Siraj M; McMahon Caitlin; Miller VincentLung cancer (Amsterdam, Netherlands) (2015), 89 (1), 76-9 ISSN:.In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1-2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood-brain barrier penetration. A co-administration strategy to enhance the brain accumulation of vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood-brain barrier penetration. We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood-brain barrier penetration. A 74-year-old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5'RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood-brain barrier penetration by vandetanib in combination with everolimus. Further research is required in this setting.
- 53Reardon, D. A.; Pan, E.; Fan, J.; Mink, J.; Barboriak, D. P.; Vrendenburgh, J. J.; Desjardins, A.; Peters, K.; O’Brien, J. P.; Wen, P. Y. A phase 2 trial of the multitargeted kinase inhibitor lenvatinib (E7080) in patients with recurrent glioblastoma (GBM) and disease progression following prior bevacizumab treatment Ann. Oncol. 2012, 23 (Suppl. 9) 417PD
- 54Minocha, M.; Khurana, V.; Qin, B.; Pal, D.; Mitra, A. K. Co-administration strategy to enhance brain accumulation of vandetanib by modulating P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp1/Abcg2) mediated efflux with m-TOR inhibitors Int. J. Pharm. 2012, 434, 306– 314 DOI: 10.1016/j.ijpharm.2012.05.028[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVOis7zE&md5=ffd8765aeae0cdb94b7db0a7b775caebCo-administration strategy to enhance brain accumulation of vandetanib by modulating P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp1/Abcg2) mediated efflux with m-TOR inhibitorsMinocha, Mukul; Khurana, Varun; Qin, Bin; Pal, Dhananjay; Mitra, Ashim K.International Journal of Pharmaceutics (Amsterdam, Netherlands) (2012), 434 (1-2), 306-314CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)The objectives of this study were (i) to characterize the interaction of vandetanib with P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp1) in vitro and in vivo (ii) to study the modulation of P-gp and BCRP mediated efflux of vandetanib with specific transport inhibitors and m-TOR inhibitors, everolimus and temsirolimus. Cellular accumulation and bi-directional transport studies in MDCKII cell monolayers were conducted to delineate the role of efflux transporters on disposition of vandetanib. Brain distribution studies were conducted in male FVB wild-type mice with vandetanib administered i.v. either alone or in the presence of specific inhibitors and m-TOR inhibitors. In vitro studies suggested that vandetanib is a high affinity substrate of Bcrp1 but is not transported by P-gp. Interestingly, in vivo brain distribution studies in FVB wild type mice indicated that vandetanib penetration into the brain is restricted by both Bcrp1 and P-gp mediated active efflux at the blood brain barrier (BBB). Co-administration of elacridar, a dual P-gp/BCRP inhibitor increased the brain to plasma concn. ratio of vandetanib up to 5 fold. Of the two m-TOR pathway inhibitors examd., everolimus showed potent effect on modulating vandetanib brain penetration whereas no significant affect on vandetanib brain uptake was obsd. following temsirolimus co-administration. This finding could be clin. relevant as everolimus can provide synergistic pharmacol. effect in addn. to primary role of vandetanib efflux modulation at BBB for the treatment of brain tumors.
- 55Shumaker, R. C.; Aluri, J.; Fan, J.; Martinez, G.; Thompson, G. A.; Ren, M. Effect of fifampicin on the pharmacokinetics of lenvatinib in healthy adults Clin. Drug Invest. 2014, 34, 651– 659 DOI: 10.1007/s40261-014-0217-y[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFCqu7fN&md5=2d765646adf628f301c7c3a362683dc9Effect of Rifampicin on the Pharmacokinetics of Lenvatinib in Healthy AdultsShumaker, Robert C.; Aluri, Jagadeesh; Fan, Jean; Martinez, Gresel; Thompson, Gary A.; Ren, MinClinical Drug Investigation (2014), 34 (9), 651-659CODEN: CDINFR; ISSN:1173-2563. (Springer International Publishing AG)Background and Objectives: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor under clin. investigation in solid tumors. This study evaluated the influence of P-glycoprotein (P-gp) inhibition (single-dose rifampicin) and simultaneous cytochrome P 450 3A4 (CYP3A4)/P-gp induction (multiple-dose rifampicin) on lenvatinib pharmacokinetics. Methods: This Phase I, single-center, single-dose (lenvatinib mesylate 24 mg), open-label, sequential study enrolled 15 healthy volunteers. Three regimens were administered over three periods: Period (P) 1 (Days 1-8), P2 (Days 15-22) and P3 (Days 29-50), with a 14-day (first dose) and 28-day (second dose) washout period after lenvatinib mesylate administration (Day 1, Day 15 and Day 43). In P2, a single oral dose of rifampicin (600 mg) was coadministered with lenvatinib. In P3, rifampicin was administered daily (600 mg) for 21 days (Days 29-49). Serial blood samples were collected, and plasma concns. of total (protein bound + unbound) and free (unbound) lenvatinib and total metabolites (M1, M2, M3 and M5) were measured by validated high-performance liq. chromatog./tandem mass spectrometry. Results: Single-dose rifampicin (P-gp inhibition) increased area under the plasma concn.-time curve from time zero to infinity (AUC0-∞) of free and total lenvatinib by 32 and 31 %, resp. Multiple-dose rifampicin (simultaneous P-gp and CYP3A4 induction) decreased lenvatinib AUC0-∞ (total: 18 %; free: 9 %). Treatment-emergent adverse events were mild or moderate and occurred in 7 subjects (47 %). Conclusion: Lenvatinib exposure was increased by P-gp inhibition; however, based on free concns., simultaneous P-gp and CYP3A4 induction results met the prespecified bioequivalence 90 % confidence interval. Overall, the magnitude of these changes was relatively small, and likely not clin. meaningful.
- 56Banerjee, S.; Zvelebil, M.; Furet, P.; Mueller-Vieira, U.; Evans, D. B.; Dowsett, M.; Martin, L. A. The vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 inhibits aromatase Cancer Res. 2009, 69, 4716– 4723 DOI: 10.1158/0008-5472.CAN-08-4711
- 57(a) Gerstner, E. R.; Eichler, A. F.; Plotkin, S. R.; Drappatz; Doyle, C. L.; Xu, L.; Duda, D. G.; Wen, P. Y.; Jain, R. K.; Batchelor, T. T. Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide J. Neuro-Oncol. 2011, 103, 325– 332 DOI: 10.1007/s11060-010-0390-7[Crossref], [PubMed], [CAS], Google Scholar57ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmtl2nsLc%253D&md5=aa5ca98063908b011c83e27a952ef242Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomideGerstner, Elizabeth R.; Eichler, April F.; Plotkin, Scott R.; Drappatz, Jan; Doyle, Colin L.; Xu, Lei; Duda, Dan G.; Wen, Patrick Y.; Jain, Rakesh K.; Batchelor, Tracy T.Journal of Neuro-Oncology (2011), 103 (2), 325-332CODEN: JNODD2; ISSN:0167-594X. (Springer)Targeting angiogenesis in glioblastoma (GBM) may improve patient outcome by normalizing tumor vasculature and improving delivery of chemotherapeutics and oxygen. Consequently, concomitant administration of small mol. inhibitors of the VEGF pathway will likely have a pos. impact on chemoradiation treatment outcome. We conducted a Phase I study of vatalanib, a small mol. inhibitor of VEGFR, PDGFR, and c-kit in patients with newly diagnosed GBM receiving radiation, temozolomide, and an enzyme-inducing anti-epileptic drug in order to det. the MTD of vatalanib in this patient population. We incorporated circulating biomarker and SNP analyses and pharmacokinetic studies. Nineteen patients were enrolled and the MTD was not reached at the time of study termination. Vatalanib was well tolerated with only 2 DLTs (thrombocytopenia and elevated transaminases). Other grade 3/4 toxicities included leukopenia, lymphopenia, neutropenia, and hand-foot syndrome. There were no wound-healing complications. Of the 13 patients evaluable for a radiog. response, 2 had a partial response and 9 had stable disease. Vatalanib significantly increased PlGF and sVEGFR1 in plasma circulation and decreased sVEGFR2 and sTie2. Plasma collagen IV increased significantly by day 50 of treatment. Vatalanib was well tolerated and this study demonstrates the safety of oral small mol. inhibitors in newly diagnosed GBM patients. Blood biomarkers may be useful as pharmacodynamic markers of response to anti-angiogenic therapies.(b) Brandes, A. A.; Stupp, R.; Hau, P.; Lacombe, D.; Gorlia, T.; Tosoni, A.; Mirimanoff, R. O.; Kros, J. M.; van den Bent, M. J. EORTC study 26041-22041: phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma Eur. J. Cancer 2010, 46, 348– 354 DOI: 10.1016/j.ejca.2009.10.029(c) Reardon, D. A.; Egorin, M. J.; Desjardins, A.; Vredenburgh, J. J.; Beumer, J. H.; Lagattuta, T. F.; Gururangan, S.; Herndon, J. E.; Salvado, A. J.; Friedman, H. S. Phase I pharmacokinetic study of the VEGFR tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma Cancer 2009, 115, 2188– 2198 DOI: 10.1002/cncr.24213
- 58Yakes, F. M.; Chen, J.; Tan, J.; Yamaguchi, K.; Shi, Y.; Yu, P.; Qian, F.; Chu, F.; Bentzien, F.; Cancilla, B.; Orf, J.; You, A.; Laird, A. D.; Engst, S.; Lee, L.; Lesch, J.; Chou, Y. C.; Joly, A. H. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth Mol. Cancer Ther. 2011, 10, 2298– 2308 DOI: 10.1158/1535-7163.MCT-11-0264[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFylurnF&md5=3f573795ecee42deeee25005f991868fCabozantinib (XL184), a Novel MET and VEGFR2 Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and Tumor GrowthYakes, F. Michael; Chen, Jason; Tan, Jenny; Yamaguchi, Kyoko; Shi, Yongchang; Yu, Peiwen; Qian, Fawn; Chu, Felix; Bentzien, Frauke; Cancilla, Belinda; Orf, Jessica; You, Andrew; Laird, A. Douglas; Engst, Stefan; Lee, Lillian; Lesch, Justin; Chou, Yu-Chien; Joly, Alison H.Molecular Cancer Therapeutics (2011), 10 (12), 2298-2308CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a no. of human malignancies and has been assocd. with tumorigenesis. Cabozantinib (XL184) is a small-mol. kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a no. of other receptor tyrosine kinases that have also been implicated in tumor pathobiol., including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant redns. in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathol., resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an exptl. model of metastasis, which has been obsd. with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. Mol Cancer Ther; 10(12); 2298-308.
- 59Bhide, R. S.; Cai, Z. W.; Zhang, Y. Z.; Qian, L.; Wei, D.; Barbosa, S.; Lombardo, L. J.; Borzilleri, R. M.; Zheng, X.; Wu, L. I.; Barrish, J. C.; Kim, S. H.; Leavitt, K.; Mathur, A.; Leith, L.; Chao, S.; Wautlet, B.; Mortillo, S.; Jeyaseelan, R.; Kukral, D.; Hunt, J. T.; Kamath, A.; Fura, A.; Vyas, V.; Marathe, P.; D’Arienzo, C.; Derbin, G.; Fargnoli, J. Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor J. Med. Chem. 2006, 49, 2143– 2146 DOI: 10.1021/jm051106d
- 60Highlights of Prescribing Information. COMETRIQ. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf (accessed June 12, 2016) .
- 61Marathe, P. H.; Kamath, A. V.; Zhang, Y.; D’Arienzo, C.; Bhide, R.; Fargnoli, J. Preclinical pharmacokinetics and in vitro metabolism of brivanib (BMS-540215), a potent VEGFR2 inhibitor and its alanine ester prodrug brivanib alaninate Cancer Chemother. Pharmacol. 2009, 65, 55– 66 DOI: 10.1007/s00280-009-1002-0[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFegu77K&md5=d7ca6c43910437a12f64d70fe12c6e9cPreclinical pharmacokinetics and in vitro metabolism of brivanib (BMS-540215), a potent VEGFR2 inhibitor and its alanine ester prodrug brivanib alaninateMarathe, Punit H.; Kamath, Amrita V.; Zhang, Yueping; D'Arienzo, Celia; Bhide, Rajeev; Fargnoli, JosephCancer Chemotherapy and Pharmacology (2009), 65 (1), 55-66CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Brivanib alaninate is a prodrug of brivanib (BMS-540215), a potent oral VEGFR-2 inhibitor and is currently in development for the treatment of hepatocellular and colon carcinomas. In vitro and in vivo studies were conducted to characterize the preclin. pharmacokinetics and disposition of brivanib and brivanib alaninate, and antitumor efficacy in mice bearing human xenografts. In vitro studies were conducted in liver and intestinal fractions, plasma and Caco-2 cells to assess the metabolic stability. Pharmacokinetics of brivanib were detd. in preclin. species after administration of single i.v. or oral doses of both brivanib and brivanib alaninate. The antitumor efficacy was assessed at equimolar doses in nude mice bearing human tumor xenografts. Human efficacious dose was predicted based on projected human pharmacokinetic parameters and exposure at efficacious doses in the mouse efficacy models. In vitro and in vivo studies indicated that brivanib alaninate was efficiently converted to brivanib. Brivanib showed good brain penetration in rats consistent with its high intrinsic permeability and lack of active efflux in Caco-2 cells. The oral bioavailability of brivanib varied among species (22-88%) and showed dissoln. rate-limited absorption even when combined with org. co-solvents. Administration of brivanib as brivanib alaninate allowed completely aq. vehicles, and an improvement in the oral bioavailability (55-97%) was obsd. The clearance of brivanib in humans is anticipated to be low to intermediate (hepatic extn. ratio < 0.7), while its vol. of distribution is expected to be high. The min. efficacious dose of brivanib alaninate was detd. to be 60 mg/kg per day. Brivanib alaninate is rapidly and efficiently converted to the parent, brivanib, as demonstrated both in vitro and in vivo and offers an excellent mode to deliver brivanib orally.
- 62(a) De Groot, J. F.; Prados, M.; Urquhart, T.; Robertson, S.; Yaron, Y.; Sorensen, A. G.; Norton, A.; Batchelor, T.; Drappatz, J.; Wen, P. A phase II study of XL184 in patients (pts) with progressive glioblastoma multiforme (GBM) in first or second relapse J. Clin. Oncol. 2009, 27 (15s) 2047(b) Wen, P. Y.; Prados, M.; Schiff, D.; Reardon, D. A.; Cloughesy, T.; Mikkelsen, T.; Batchelor, T.; Drappatz, J.; Chamberlain, M. C.; De Groot, J. F. Phase II study of XL184 (BMS 907351), an inhibitor of MET, VEGFR2, and RET, in patients (pts) with progressive glioblastoma (GB) J. Clin. Oncol. 2010, 28, 2006
- 63Dowell, J.; Minna, J. D.; Kirkpatrick, P. Erlotinib hydrochloride Nat. Rev. Drug Discovery 2005, 4, 13– 14 DOI: 10.1038/nrd1612[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlsl2n&md5=acb463aa1a7ad35b770490a7c82800cdFresh from the Pipeline: Erlotinib hydrochlorideDowell, Jonathan; Minna, John D.; Kirkpatrick, PeterNature Reviews Drug Discovery (2005), 4 (1), 13-14CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)Erlotinib hydrochloride (Tarceva; OSI Pharmaceuticals/Genentech/Roche), a member of a class of targeted anticancer drugs that inhibit the activity of the epidermal growth factor receptor, was approved by the US FDA in Nov. 2004 for the treatment of advanced non-small-cell lung cancer after failure of at least one prior chemotherapy regimen. It is the first such drug to demonstrate an increase in survival in Phase III trials in patients with advanced non-small-cell lung cancer.
- 64Muhsin, M.; Graham, J.; Kirkpatrick, P. Gefitinib Nat. Rev. Drug Discovery 2003, 2, 515– 516 DOI: 10.1038/nrd1136[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXks1Oqsr0%253D&md5=e9fb650f4d801eb2026a795db1b9f6bdFresh from the pipeline: GefitinibMuhsin, Mohamed; Graham, Joanne; Kirkpatrick, PeterNature Reviews Drug Discovery (2003), 2 (7), 515-516CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)Gefitinib (Iressa; AstraZeneca) is the first in a new class of targeted anticancer drugs that inhibit the tyrosine kinase activity of the epidermal growth factor receptor. Following Japanese approval in 2002, gefitinib was approved by the US FDA in May 2003 for the treatment of advanced non-small-cell lung cancer after other treatment options have failed. Despite several setbacks during the development of gefitinib, might it now be back on the path to blockbuster status.
- 65Eskens, F. A. L. M.; Mom, C. H.; Planting, A. S. T.; Gieterma, J. A.; Amelsberg, A.; Huisman, H.; van Doorn, L.; Burger, H.; Stopfer, P.; Verweij, J.; de Vries, E. G. E. A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor I (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumors Br. J. Cancer 2008, 98, 80– 85 DOI: 10.1038/sj.bjc.6604108[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXisF2qtg%253D%253D&md5=96a0be31145bf1691640109d69ff5dc0A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumorsEskens, F. A. L. M.; Mom, C. H.; Planting, A. S. T.; Gietema, J. A.; Amelsberg, A.; Huisman, H.; van Doorn, L.; Burger, H.; Stopfer, P.; Verweij, J.; de Vries, E. G. E.British Journal of Cancer (2008), 98 (1), 80-85CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clin. activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhea despite treatment and grade 2 diarrhea lasting more than 7 days despite treatment). An addnl. 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics anal. in skin biopsies did not show significant changes in EGFR-assocd. biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was obsd. No partial or complete responses were obsd., stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD. British Journal of Cancer (2008) 98, 80-85. doi:10.1038/sj.bjc.6604108 www.bjcancer.com Published online 20 Nov. 2007.
- 66Finlay, M. R. V.; Anderton, M.; Ashton, S.; Ballard, P.; Bethel, P. A.; Box, M. R.; Bradbury, R. H.; Brown, S. J.; Butterworth, S.; Campbell, A.; Chorley, C.; Colclough, N.; Cross, D. A. E.; Currie, G. S.; Grist, M.; Hassall, L.; Hill, G. B.; James, D.; James, M.; Kemmitt, P.; Klinowska, T.; Lamont, G.; Lamont, S. G.; Martin, N.; McFarland, H. L.; Mellor, M. J.; Orme, J. P.; Perkins, D.; Perkins, P.; Richmond, G.; Smith, P.; Ward, R. A.; Waring, M. J.; Whittaker, D.; Wells, S.; Wrigley, G. L. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor J. Med. Chem. 2014, 57, 8249– 8267 DOI: 10.1021/jm500973a[ACS Full Text], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1KhurrI&md5=db9db624bb4324c2e22b1ab12035263bDiscovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the ReceptorFinlay, M. Raymond V.; Anderton, Mark; Ashton, Susan; Ballard, Peter; Bethel, Paul A.; Box, Matthew R.; Bradbury, Robert H.; Brown, Simon J.; Butterworth, Sam; Campbell, Andrew; Chorley, Christopher; Colclough, Nicola; Cross, Darren A. E.; Currie, Gordon S.; Grist, Matthew; Hassall, Lorraine; Hill, George B.; James, Daniel; James, Michael; Kemmitt, Paul; Klinowska, Teresa; Lamont, Gillian; Lamont, Scott G.; Martin, Nathaniel; McFarland, Heather L.; Mellor, Martine J.; Orme, Jonathon P.; Perkins, David; Perkins, Paula; Richmond, Graham; Smith, Peter; Ward, Richard A.; Waring, Michael J.; Whittaker, David; Wells, Stuart; Wrigley, Gail L.Journal of Medicinal Chemistry (2014), 57 (20), 8249-8267CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Epidermal growth factor receptor (EGFR) inhibitors have been used clin. in the treatment of nonsmall-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a no. of years. Despite encouraging clin. efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addn., EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. The authors describe herein the evolution of an early, mutant selective lead to the clin. candidate AZD9291 I, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclin. models, the clin. candidate was administered clin. to patients with T790M pos. EGFR-TKI resistant NSCLC and early efficacy has been obsd., accompanied by an encouraging safety profile.
- 67(a) Bartolotti, M.; Franceschi, E.; Brandes, A. A. EGF receptor tyrosine kinase inhibitors in the treatment of brain metastases from non-small-cell lung cancer Expert Rev. Anticancer Ther. 2012, 12, 1429– 1435 DOI: 10.1586/era.12.121[Crossref], [PubMed], [CAS], Google Scholar67ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVClu73N&md5=ab9824f9a0881ffae33f9765d8a43b97EGF receptor tyrosine kinase inhibitors in the treatment of brain metastases from non-small-cell lung cancerBartolotti, Marco; Franceschi, Enrico; Brandes, Alba ArielaExpert Review of Anticancer Therapy (2012), 12 (11), 1429-1435CODEN: ERATBJ; ISSN:1473-7140. (Expert Reviews Ltd.)A review. The incidence of brain metastasis (BM) is high in patients with non-small-cell lung cancer. Available std. therapeutic options, such as whole-brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. Novel agents, such as EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs), have now been included in std. non-small-cell lung cancer treatments. In a small subset of patients harboring EGFR-activating mutations, erlotinib and gefitinib administration was followed by a response rate of 70-80%, and a longer progression-free and overall survival than those obtained with std. chemotherapeutic regimens. However, since most of the larger studies on these agents have excluded BM patients from their series, few prospective data are available on the efficacy of these agents in this setting. In recent years, however, several authors have reported a growing no. of cases of partial and complete response in BM patients treated with EGFR TKIs. Data from retrospective series and Phase II studies also suggest that a response can be obtained using EGFR TKI treatment for patients with BM, esp. those harboring EGFR mutations.(b) Shimato, S.; Mitsudomi, T.; Kosaka, T.; Yatabe, Y.; Wakabayashi, T.; Mizuno, M.; Nakahara, N.; Hatano, H.; Natsume, A.; Ishii, D.; Yoshida, J. EGFR mutations in patients with brain metastases from lung cancer: association with the efficacy of gefitinib Neuro-Oncology 2006, 8, 137– 144 DOI: 10.1215/15228517-2005-002(c) Porta, R.; Sanchez-Torres, J. M.; Paz-Ares, L.; Massuti, B.; Reguart, N.; Mayo, C.; Lianes, P.; Queralt, C.; Guillem, V.; Salinas, P.; Catot, S.; Isla, D.; Pradas, A.; Gurpide, A.; de Castro, J.; Polo, E.; Puig, T.; Taron, M.; Colomer, R.; Rosell, R. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation Eur. Respir. J. 2011, 37, 624– 631 DOI: 10.1183/09031936.00195609[Crossref], [PubMed], [CAS], Google Scholar67chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmslemtLo%253D&md5=76106616b8b799d191c697b9295993baBrain metastases from lung cancer responding to erlotinib: the importance of EGFR mutationPorta, R.; Sanchez-Torres, J. M.; Paz-Ares, L.; Massuti, B.; Reguart, N.; Mayo, C.; Lianes, P.; Queralt, C.; Guillem, V.; Salinas, P.; Catot, S.; Isla, D.; Pradas, A.; Gurpide, A.; de Castro, J.; Polo, E.; Puig, T.; Taron, M.; Colomer, R.; Rosell, R.European Respiratory Journal (2011), 37 (3), 624-631CODEN: ERJOEI; ISSN:0903-1936. (European Respiratory Society)Median survival of patients with brain metastases from nonsmall cell lung cancer (NSCLC) is poor and more effective treatments are urgently needed. We have evaluated the efficacy of erlotinib in this setting and its assocn. with activating mutations in the epidermal growth factor receptor (EGFR) gene. We retrospectively identified patients with NSCLC and brain metastases treated with erlotinib. EGFR mutations in exons 19 and 21 were analyzed by direct sequencing. Efficacy and tolerability were compared according to EGFR mutational status. 69 NSCLC patients with brain metastases were identified, 17 of whom harbored EGFR mutations. Objective response rate in patients with EGFR mutations was 82.4%; no responses were obsd. in unselected patients (p<0.001). Median (95% CI) time to progression within the brain for patients harboring EGFR mutations was 11.7 (7.9-15.5) months, compared to 5.8 (5.2-6.4) months for control patients whose EGFR mutational status had not been assessed (p<0.05). Overall survival was 12.9 (6.2-19.7) months and 3.1 (2.5-3.9) months (p<0.001), resp. The toxicity of erlotinib was as expected and no differences between cohorts were obsd. Erlotinib is active in brain metastases from NSCLC; this clin. benefit is related to the presence of activating mutations in exons 19 or 21 of the EGFR gene.(d) Grommes, C.; Oxnard, G. R.; Kris, M. G.; Miller, V. A.; Pao, W.; Holodny, A. I.; Clarke, J. L.; Lassman, A. B. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer Neuro-Oncology 2011, 13, 1364– 1369 DOI: 10.1093/neuonc/nor121(e) Jackman, D. M.; Holmes, A. J.; Lindeman, N.; Wen, P. Y.; Kesari, S.; Borras, A. M.; Bailey, C.; de Jong, F.; Janne, P. A.; Johnson, B. E. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib J. Clin. Oncol. 2006, 24, 4517– 4520 DOI: 10.1200/JCO.2006.06.6126[Crossref], [PubMed], [CAS], Google Scholar67ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28rlslemtA%253D%253D&md5=391e78d72a39626276f7ffcbee76d1a1Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinibJackman David M; Holmes Alison J; Lindeman Neal; Wen Patrick Y; Kesari Santosh; Borras Ana M; Bailey Christopher; de Jong Francisca; Janne Pasi A; Johnson Bruce EJournal of clinical oncology : official journal of the American Society of Clinical Oncology (2006), 24 (27), 4517-20 ISSN:.There is no expanded citation for this reference.(f) Park, S. J.; Kim, H. T.; Lee, D. H.; Kim, K. P.; Kim, S.-W.; Suh, C.; Lee, J. S. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation Lung Cancer. 2012, 77, 556– 560 DOI: 10.1016/j.lungcan.2012.05.092
- 68Noronha, V.; Joshi, A.; Gokarn, A.; Sharma, V.; Patil, V.; Janu, A.; Purandare, N.; Chougule, A.; Jambhekar, N.; Prabhash, K. The importance of brain metastasis in EGFR mutation positive NSCLC patients Chemother. Res. Pract. 2014, 2014, 856156 DOI: 10.1155/2014/856156[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mvis1ykug%253D%253D&md5=fdb159a058dda4901c526fc0e9403138The Importance of Brain Metastasis in EGFR Mutation Positive NSCLC PatientsNoronha Vanita; Joshi Amit; Gokarn Anant; Sharma Vibhor; Chougule Anuradha; Prabhash Kumar; Patil Vijay; Janu Amit; Purandare Nilendu; Jambhekar NirmalaChemotherapy research and practice (2014), 2014 (), 856156 ISSN:2090-2107.Introduction. Brain metastasis is a poor prognostic marker in lung cancer. However it is not known whether amongst patients with EGFR mutation those with brain metastases have a worse outcome. Methods. We compared the survival outcomes between EGFR mutation positive patients with and without brain metastases. In this retrospective analysis of prospective database of all metastatic lung cancer patients at our centre between July 2009 and December 2012, patients were treated with either combination chemotherapy or oral TKI. All patients with brain metastases received whole brain radiation. Kaplan Meier method was used for survival analysis and compared using log rank test. Results. 101 patients with EGFR mutated, metastatic lung cancer were studied. Fourteen had brain metastases and 87 did not. The common EGFR mutations were exon 19 deletion (61.3%) and exon 21 L858R mutation (28.7%). Overall response was 64% in extracranial metastasis group as compared to 50% in brain metastasis group. There was a significant worsening of median OS in the patients with brain metastases (11.6 months) compared with only extracranial metastases (18.7 months), P = 0.029. Conclusion. Amongst patients with EGFR mutant NSCLC, the presence of brain metastases leads to a worse outcome as compared to patients with extracranial metastases alone.
- 69Weber, B.; Winterdahl, M.; Memon, A.; Sorensen, B. S.; Keiding, S.; Sorensen, L.; Nexo, E.; Meldgaard, P. Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor J. Thorac. Oncol. 2011, 6, 1287– 1289 DOI: 10.1097/JTO.0b013e318219ab87[Crossref], [PubMed], [CAS], Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MjmvV2rsA%253D%253D&md5=a00d4acc3aec6b71157da49fdf4732f0Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptorWeber Britta; Winterdahl Michael; Memon Ashfaque; Sorensen Boe S; Keiding Susanne; Sorensen Leif; Nexo Ebba; Meldgaard PeterJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (2011), 6 (7), 1287-9 ISSN:.INTRODUCTION: Drugs directed toward the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva®) and gefitinib (Iressa®), are used for the treatment of patients with advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. However, whether erlotinib actually enters into brain metastases has not been adequately elucidated. In this study, we investigated the accumulation of [11C]-erlotinib by positron emission tomography (PET) combined with computed tomography (CT) and magnetic resonance imaging (MRI). METHODS: A 32-year-old patient with NSCLC and multiple brain metastases was treated with first-line erlotinib. EGFR mutations were determined by analyzing a fine-needle lung tumor biopsy taken before the treatment. A PET/CT of the brain with [11C]-erlotinib was performed during treatment, and a MRI of the head and a CT of the chest were performed pre- and posttreatment. RESULTS: The primary lung tumor displayed an erlotinib-sensitizing exon 19 deletion in the EGFR gene, and [11C]-erlotinib PET/CT showed accumulation in the brain metastases. Posttreatment MRI and CT demonstrated regression of both brain metastases and primary lung tumor. CONCLUSION: Our data demonstrated that erlotinib accumulated in brain metastases in a NSCLC patient who responded to the treatment.
- 70Agarwal, S.; Manchanda, P.; Vogelbaum, M. A.; Ohlfest, J. R.; Elmquist, W. F. Function of the blood-brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma Drug Metab. Dispos. 2013, 41, 33– 39 DOI: 10.1124/dmd.112.048322
- 71Agarwal, S.; Sane, R.; Gallardo, J. L.; Ohlfest, J. R.; Elmquist, W. F. Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux J. Pharmacol. Exp. Ther. 2010, 334, 147– 155 DOI: 10.1124/jpet.110.167601[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXos1KltL8%253D&md5=ec97aadff2ab755740b1e6860126f71eDistribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active effluxAgarwal, Sagar; Sane, Ramola; Gallardo, Jose L.; Ohlfest, John R.; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2010), 334 (1), 147-155CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)Gefitinib is an orally active inhibitor of the epidermal growth factor receptor approved for use in patients with locally advanced or metastatic non-small cell lung cancer. It has also been evaluated in several clin. trials for treatment of brain tumors such as high-grade glioma. In this study, we investigated the influence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) on distribution of gefitinib to the central nervous system. In vitro studies conducted in Madin-Darby canine kidney II cells indicate that both P-gp and BCRP effectively transport gefitinib, limiting its intracellular accumulation. In vivo studies demonstrated that transport of gefitinib across the blood-brain barrier (BBB) is significantly limited. Steady-state brain-to-plasma (B/P) concn. ratios were 70-fold higher in the Mdr1a/b(-/-) Bcrp1(-/-) mice (ratio of approx. 7) compared with wild-type mice (ratio of approx. 0.1). The B/P ratio after oral administration increased significantly when gefitinib was coadministered with the dual P-gp and BCRP inhibitor elacridar. We investigated the integrity of tight junctions in the Mdr1a/b(-/-) Bcrp1(-/-) mice and found no difference in the brain inulin and sucrose space between the wild-type and Mdr1a/b(-/-) Bcrp1(-/-) mice. This suggested that the dramatic enhancement in the brain distribution of gefitinib is not due to a leakier BBB in these mice. These results show that brain distribution of gefitinib is restricted due to active efflux by P-gp and BCRP. This finding is of clin. significance for therapy in brain tumors such as glioma, where concurrent administration of a dual inhibitor such as elacridar can increase delivery and thus enhance efficacy of gefitinib.
- 72Peters, S.; Zimmerman, S.; Adjei, A. A. Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug-drug interactions Cancer Treat. Rev. 2014, 40, 917– 926 DOI: 10.1016/j.ctrv.2014.06.010[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFGmtbrP&md5=31253f81e203aa012a5d87ad29ff6fc3Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: Comparative pharmacokinetics and drug-drug interactionsPeters, Solange; Zimmermann, Stefan; Adjei, Alex A.Cancer Treatment Reviews (2014), 40 (8), 917-926CODEN: CTREDJ; ISSN:0305-7372. (Elsevier Ltd.)A review. The development of orally active small mol. inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients with activating mutations of the EGFR gene show sensitivity to, and clin. benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50-60% of cases being related to the appearance of a T790M gatekeeper mutation. Newer, irreversible EGFR-TKls - afatinib and dacomitinib - covalently bind to and inhibit multiple receptors in the ErbB family (EGFR, HER2 and HER4). These agents have been mainly evaluated for first-line treatment but also in the setting of acquired resistance to first-generation EGFR-TKls. Afatinib is the first ErbB family blocker approved for patients with NSCLC with activating EGFR mutations; dacomitinib is in late stage clin. development. Mutant-selective EGFR inhibitors (AZD9291, CO-1686, HM61713) that specifically target the T790M resistance mutation are in early development. The EGFR-TKIs differ in their spectrum of target kinases, reversibility of binding to EGFR receptor, pharmacokinetics and potential for drug-drug interactions, as discussed in this review. For the clinician, these differences are relevant in the setting of polymedicated patients with NSCLC, as well as from the perspective of innovative anticancer drug combination strategies.
- 73Highlights of Prescribing Information. TAGRISSO. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf Accessed June 12, 2016.
- 74Hoffknecht, P.; Tufman, A.; Wehler, T.; Pelzer, T.; Wiewrodt, R.; Schutz, M.; Serke, M.; Stohlmacher-Williams, J.; Marten, A.; Huber, R. M.; Dickgreber, N. J. Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease J. Thorac. Oncol. 2015, 10, 156– 163 DOI: 10.1097/JTO.0000000000000380[Crossref], [PubMed], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXisF2gsb4%253D&md5=90100bf9781e109f52c6498858c84ef3Efficacy of the Irreversible ErbB Family Blocker Afatinib in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI)-Pretreated Non-Small-Cell Lung Cancer Patients with Brain Metastases or Leptomeningeal DiseaseHoffknecht, Petra; Tufman, Amanda; Wehler, Thomas; Pelzer, Theo; Wiewrodt, Rainer; Schuetz, Martin; Serke, Monika; Stoehlmacher-Williams, Jan; Maerten, Angela; Huber, Rudolf Maria; Dickgreber, Nicolas J.Journal of Thoracic Oncology (2015), 10 (1), 156-163CODEN: JTOOB7; ISSN:1556-0864. (Lippincott Williams & Wilkins)Introduction: Afatinib is an effective first-line treatment in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) and has shown activity in patients progressing on EGFR-tyrosine kinase inhibitors (TKIs). First-line afatinib is also effective in patients with central nervous system (CNS) metastasis. Here we report on outcomes of pretreated NSCLC patients with CNS metastasis who received afatinib within a compassionate use program. Methods: Patients with NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment received afatinib. Medical history, patient demographics, EGFR mutational status, and adverse events including tumor progression were documented. Results: From 2010 to 2013, 573 patients were enrolled and 541 treated with afatinib. One hundred patients (66% female; median age, 60 years) had brain metastases and/or leptomeningeal disease with 74% having documented EGFR mutation. Median time to treatment failure for patients with CNS metastasis was 3.6 mo, and did not differ from a matched group of 100 patients without CNS metastasis. Thirty-five percent (11 of 31) of evaluable patients had a cerebral response, five (16%) responded exclusively in brain. Response duration (range) was 120 (21-395) days. Sixty-six percent (21 of 32) of patients had cerebral disease control on afatinib. Data from one patient with an impressive response showed an afatinib concn. in the cerebrospinal fluid of nearly 1 nMol. Conclusion: Afatinib appears to penetrate into the CNS with concns. high enough to have clin. effect on CNS metastases. Afatinib may therefore be an effective treatment for heavily pretreated patients with EGFR-mutated or EGFR-TKI-sensitive NSCLC and CNS metastasis.
- 75Hatanpaa, K. J.; Burma, S.; Zhao, D.; Habib, A. A. Epidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance Neoplasia 2010, 12, 675– 684 DOI: 10.1593/neo.10688
- 76(a) Mellinghoff, I. K.; Wang, M. Y.; Vivanco, I.; Haas-Kogan, D. A.; Zhu, S.; Dia, E. Q.; Lu, K. V.; Yoshimoto, K.; Huang, J. H. Y.; Chute, D. J.; Riggs, B. L.; Horvatch, S.; Liau, L. M.; Cavanee, W. K.; Rao, P. N.; Beroukhim, R.; Peck, T. C.; Lee, J. C.; Sellers, W. R.; Stokoe, D.; Prados, M.; Cloughesy, T. F.; Sawyers, C. L.; Mischel, P. S. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors N. Engl. J. Med. 2005, 353, 2012– 2024 DOI: 10.1056/NEJMoa051918[Crossref], [PubMed], [CAS], Google Scholar76ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1SrtrrE&md5=e19cb1d6924c5019a7ed5d5f1ccdb6d0Molecular determinants of the response of glioblastomas to EGFR kinase inhibitorsMellinghoff, Ingo K.; Wang, Maria Y.; Vivanco, Igor; Haas-Kogan, Daphne A.; Zhu, Shaojun; Dia, Ederlyn Q.; Lu, Kan V.; Yoshimoto, Koji; Huang, Julie H. Y.; Chute, Dennis J.; Riggs, Bridget L.; Horvath, Steve; Liau, Linda M.; Cavenee, Webster K.; Rao, P. Nagesh; Beroukhim, Rameen; Peck, Timothy C.; Lee, Jeffrey C.; Sellers, William R.; Stokoe, David; Prados, Michael; Cloughesy, Timothy F.; Sawyers, Charles L.; Mischel, Paul S.New England Journal of Medicine (2005), 353 (19), 2012-2024CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 % of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. We sequenced kinase domains in the EGFR and human EGFR type 2 (Her21neu) genes and analyzed the expression of EGFR, EGFR deletion mutantvariant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We detd. the mol. correlates of clin. response, validated them in an independent data set, and identified effects of the mol. abnormalities in vitro. Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 %. Pretreatment tissue was available for mol. anal. from 26 patients, 7 of whom had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly assocd. with a clin. response (P <0.001; odds ratio, 51; 95 % confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P = 0.001; odds ratio, 40; 95 % confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib. Coexpression of EGFRvIII and PTEN by glioblastoma cells is assocd. with responsiveness to EGFR kinase inhibitors.(b) Rich, J. N.; Reardon, D. A.; Peery, T.; Dowell, J. M.; Quinn, J. A.; Penne, K. L.; Wikstrand, C. J.; Van Duyn, L. B.; Dancey, J. E.; McLendon, R. E.; Kao, J. C.; Stenzel, T. T.; Rasheed, B. K. A.; Tourt-Uhlig, S. E.; Herndon, J. E.; Vredenburgh, J. J.; Sampson, J. H.; Friedman, A. H.; Bigner, D. D.; Friedman, H. S. Phase II trial of gefitinib in recurrent glioblastoma J. Clin. Oncol. 2004, 22, 133– 142 DOI: 10.1200/JCO.2004.08.110[Crossref], [PubMed], [CAS], Google Scholar76bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpsVKhsr8%253D&md5=4477591e92c2ce1272a21b1bbf8e451aPhase II trial of gefitinib in recurrent glioblastomaRich, Jeremy N.; Reardon, David A.; Peery, Terry; Dowell, Jeannette M.; Quinn, Jennifer A.; Penne, Kara L.; Wikstrand, Carol J.; van Duyn, Lauren B.; Dancey, Janet E.; McLendon, Roger E.; Kao, James C.; Stenzel, Timothy T.; Rasheed, B. K. Ahmed; Tourt-Uhlig, Sandra E.; Herndon, James E., II; Vredenburgh, James J.; Sampson, John H.; Friedman, Allan H.; Bigner, Darell D.; Friedman, Henry S.Journal of Clinical Oncology (2004), 22 (1), 133-142CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)The aim was to evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-wk cycles, and the 6-mo event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 wk, and the median overall survival (OS) time from treatment initiation was 39.4 wk. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea pos. predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.
- 77Walter, A. O.; Sjin, R. T.; Haringsma, H. J.; Ohashi, K.; Sun, J.; Lee, K.; Dubrovsky, A.; Labenski, M.; Zhu, Z.; Wang, Z.; Sheets, M.; St Martin, T.; Karp, R.; van Kalken, D.; Chaturvedi, P.; Niu, D.; Nacht, M.; Petter, R. C.; Westlin, W.; Lin, K.; Jaw-Tsai, S.; Raponi, M.; Van Dyke, T.; Etter, J.; Weaver, Z.; Pao, W.; Singh, J.; Simmons, A. D.; Harding, T. C.; Allen, A. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC Cancer Discovery 2013, 3, 1404– 1415 DOI: 10.1158/2159-8290.CD-13-0314[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvV2rtLvN&md5=3d111f4bf958f2fda6890fbc0e1d99f5Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLCWalter, Annette O.; Sjin, Robert Tjin Tham; Haringsma, Henry J.; Ohashi, Kadoaki; Sun, Jing; Lee, Kwangho; Dubrovskiy, Aleksandr; Labenski, Matthew; Zhu, Zhendong; Wang, Zhigang; Sheets, Michael; St. Martin, Thia; Karp, Russell; van Kalken, Dan; Chaturvedi, Prasoon; Niu, Deqiang; Nacht, Mariana; Petter, Russell C.; Westlin, William; Lin, Kevin; Jaw-Tsai, Sarah; Raponi, Mitch; Van Dyke, Terry; Etter, Jeff; Weaver, Zoe; Pao, William; Singh, Juswinder; Simmons, Andrew D.; Harding, Thomas C.; Allen, AndrewCancer Discovery (2013), 3 (12), 1404-1415CODEN: CDAIB2; ISSN:2159-8274. (American Association for Cancer Research)Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clin. efficacy is limited by acquired resistance, frequently driven by the EGFRT790M mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was obsd. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of addnl. mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC.
- 78(a) Yoshida, Y.; Ozawa, T.; Butowski, N.; Shen, W.; Brown, D.; Pederson, H.; James, D. Preclinical evaluation of NT-113, a novel ERBB inhibitor optimized for CNS biodistribution Neuro-Oncology 2013, 15 (Suppl.) ET-00(b) Yoshida, Y.; Ozawa, T.; Yao, T.-W.; Shen, W.; Brown, D.; Parsa, A. T.; Raizer, J. J.; Cheng, S.-Y.; Stegh, A. H.; Mazar, A. P.; Giles, F. J.; Sarkaria, J. N.; Butowski, N.; Nicolaides, T.; James, C. D. NT113, a pan-ERBB inhibitor with high brain penetrance, inhibits the growth of glioblastoma xenografts with EGFR amplification Mol. Cancer Ther. 2014, 13, 2919– 2929 DOI: 10.1158/1535-7163.MCT-14-0306[Crossref], [PubMed], [CAS], Google Scholar78bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVCju7jM&md5=b500ebf948e4eee2d604ed99d87382b9NT113, a Pan-ERBB Inhibitor with High Brain Penetrance, Inhibits the Growth of Glioblastoma Xenografts with EGFR AmplificationYoshida, Yasuyuki; Ozawa, Tomoko; Yao, Tsun-Wen; Shen, Wang; Brown, Dennis; Parsa, Andrew T.; Raizer, Jeffrey J.; Cheng, Shi-Yuan; Stegh, Alexander H.; Mazar, Andrew P.; Giles, Francis J.; Sarkaria, Jann N.; Butowski, Nicholas; Nicolaides, Theodore; James, C. DavidMolecular Cancer Therapeutics (2014), 13 (12), 2919-2929CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)This report describes results from our anal. of the activity and biodistribution of a novel pan-ERBB inhibitor, NT113, when used in treating mice with intracranial glioblastoma (GBM) xenografts. Approaches used in this investigation include: bioluminescence imaging (BLI) for monitoring intracranial tumor growth and response to therapy; detn. of survival benefit from treatment; anal. of tumor IHC reactivity for indication of treatment effect on proliferation and apoptotic response; Western blot anal. for detn. of effects of treatment on ERBB and ERBB signaling mediator activation; and high-performance liq. chromatog. for detn. of NT113 concn. in tissue exts. from animals receiving oral administration of inhibitor. Our results show that NT113 is active against GBM xenografts in which wild-type EGFR or EGFRvIII is highly expressed. In expts. including lapatinib and/or erlotinib, NT113 treatment was assocd. with the most substantial improvement in survival, as well as the most substantial tumor growth inhibition, as indicated by BLI and IHC results. Western blot anal. results indicated that NT113 has inhibitory activity, both in vivo and in vitro, on ERBB family member phosphorylation, as well as on the phosphorylation of downstream signaling mediator Akt. Results from the anal. of animal tissues revealed significantly higher NT113 normal brain-to-plasma and intracranial tumor-to-plasma ratios for NT113, relative to erlotinib, indicating superior NT113 partitioning to intracranial tissue compartments. These data provide a strong rationale for the clin. investigation of NT113, a novel ERBB inhibitor, in treating patients with GBM.
- 79Zeng, Q.; Wang, J.; Cheng, Z.; Chen, K.; Johnstrom, P.; Varnas, K.; Li, D. Y.; Yang, Z. F.; Zhang, X. Discovery and evaluation of clinical candidate AZD3759, a potent, oral active, central nervous system-penetrant, epidermal growth factor receptor tyrosine kinase inhibitor J. Med. Chem. 2015, 58, 8200– 8215 DOI: 10.1021/acs.jmedchem.5b01073[ACS Full Text], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtl2qu7rI&md5=1bfaf33c6fa94a490707b3673314eeb5Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase InhibitorZeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnstrom, Peter; Varnas, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, XiaolinJournal of Medicinal Chemistry (2015), 58 (20), 8200-8215CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recent reports suggest that an increasing no. of patients with lung cancer, esp. those with activating mutations of the epidermal growth factor receptor (EGFR), also present with brain metastases and leptomeningeal metastases. These patients have poor prognosis as there are no approved drugs for these indications. Available agents have poor efficacy for these patients even at well above their std. dose. Herein, the authors report the discovery I (AZD3759), an investigational drug currently in Phase 1 clin. trial, which has excellent central nervous system penetration and which induces profound regression of brain metastases in a mouse model.
- 80Ströbele, S.; Schneider, M.; Schneele, L.; Siegelin, M. D.; Nonnenmacher, L.; Zhou, S.; Karpel-Massle, G.; Westhoff, M.-A.; Halatsch, M.-E.; Debatin, K.-M. A potential role for the inhibition of PI3K signaling in glioblastoma therapy PLoS One 2015, 10, e0131670 DOI: 10.1371/journal.pone.0131670
- 81Akhavan, D.; Cloughesy, T. F.; Mischel, P. S. mTOR signaling in glioblastoma: lessons learned from bench to bedside Neuro-Oncology 2010, 12, 882– 889 DOI: 10.1093/neuonc/noq052
- 82The Cancer Genome Atlas Network Comprehensive genomic characterization defines human glioblastoma genes and core pathways Nature 2008, 455, 1061– 1068 DOI: 10.1038/nature07385
- 83Westhoff, M.-A.; Karpel-Massler, G.; Brühl, O.; Enzenmüller, S.; La Ferla-Brühl, K.; Siegelin, M. D.; Nonnenmacher, L.; Debatin, K.-M. A critical evaluation of PI3K inhibition in glioblastoma and neruoblastoma therapy Mol. Cell. Ther. 2014, 2, 32 DOI: 10.1186/2052-8426-2-32[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MbhvFSmuw%253D%253D&md5=f9454544b227292f5bb6a069cda03542A critical evaluation of PI3K inhibition in Glioblastoma and Neuroblastoma therapyWesthoff Mike-Andrew; Enzenmuller Stefanie; Nonnenmacher Lisa; Debatin Klaus-Michael; Karpel-Massler Georg; Bruhl Oliver; La Ferla-Bruhl Katia; Siegelin Markus DMolecular and cellular therapies (2014), 2 (), 32 ISSN:.Members of the PI3K/Akt/mTor signaling cascade are among the most frequently altered proteins in cancer, yet the therapeutic application of pharmacological inhibitors of this signaling network, either as monotherapy or in combination therapy (CT) has so far not been particularly successful. In this review we will focus on the role of PI3K/Akt/mTOR in two distinct tumors, Glioblastoma multiforme (GBM), an adult brain tumor which frequently exhibits PTEN inactivation, and Neuroblastoma (NB), a childhood malignancy that affects the central nervous system and does not harbor any classic alterations in PI3K/Akt signaling. We will argue that inhibitors of PI3K/Akt signaling can be components for potentially promising new CTs in both tumor entities, but further understanding of the signal cascade's complexity is essential for successful implementation of these CTs. Importantly, failure to do this might lead to severe adverse effects, such as treatment failure and enhanced therapy resistance.
- 84Mohd Sharial, M. S. N.; Crown, J.; Hennessy, B. T. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer Ann. Oncol. 2012, 23, 3007– 3016 DOI: 10.1093/annonc/mds200[Crossref], [PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38flslWitg%253D%253D&md5=4093d2b285b188ffe24c42d942d529d0Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancerMohd Sharial M S N; Crown J; Hennessy B TAnnals of oncology : official journal of the European Society for Medical Oncology / ESMO (2012), 23 (12), 3007-16 ISSN:.BACKGROUND: Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed. DESIGN: A literature search was performed to identify proposed mechanisms of resistance to HER2-targeted therapy and identified novel targets in clinical development for treating HER2-resistant disease. RESULTS: Proposed HER2-resistance mechanisms include impediments to HER2-inhibitor binding, signaling through alternative pathways, upregulation of signaling pathways downstream of HER2, and failure to elicit an appropriate immune response. Although continuing HER2 inhibition beyond progression may provide an additional clinical benefit, the availability of novel therapies targeting different mechanisms of action could improve outcomes. The developmental strategy with the most available data is targeting the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) pathway. The oral mTOR inhibitor everolimus has shown promising activity in combination with chemotherapy and trastuzumab in trastuzumab-refractory, advanced breast cancer. CONCLUSIONS: Non-HER2-targeted therapy is a promising means of overcoming resistance to HER2-targeted treatment. Ongoing clinical studies will provide additional information on the efficacy and safety of novel targeted therapies in HER2-resistant advanced breast cancer.
- 85Wen, P. Y.; Lee, E. Q.; Reardon, D. A.; Ligon, K. L.; Yung, W. K. A. Current clinical development of PI3K pathway inhibitors in glioblastoma Neuro-Oncology 2012, 14, 819– 829 DOI: 10.1093/neuonc/nos117
- 86Heffron, T. P.; Ndubaku, C. O.; Salphati, L.; Alicke, B.; Cheong, J.; Drobnick, J.; Edgar, K.; Gould, S. E.; Lee, L. B.; Lesnick, J. D.; Lewis, C.; Nonomiya, J.; Pang, J.; Plise, E. G.; Sideris, S.; Wallin, J.; Wang, L.; Zhang, X.; Olivero, A. G. Discovery of clinical development candidate GDC-0084, a brain penetrant inhibitor of PI3K and mTOR ACS Med. Chem. Lett. 2016, 7, 351– 356 DOI: 10.1021/acsmedchemlett.6b00005
- 87Burger, M. T.; Pecchi, S.; Wagman, A.; Ni, Z.-J.; Knapp, M.; Hendrickson, T.; Atallah, G.; Pfister, K.; Zhang, Y.; Bartulis, S.; Frazier, K.; Ng, S.; Smith, A.; Verhagen, J.; Haznedar, J.; Huh, K.; Iwanowicz, E.; Xin, X.; Menezes, D.; Merritt, H.; Lee, I.; Wiesmann, M.; Kaufman, S.; Crawford, K.; Chin, M.; Bussiere, D.; Shoemaker, K.; Zaror, I.; Maira, S.-M.; Voliva, C. F. Identification of NVP-BKM120 as a potent, selective, orally bioavailable Class I PI3 kinase inhibitor for treating cancer ACS Med. Chem. Lett. 2011, 2, 774– 779 DOI: 10.1021/ml200156t[ACS Full Text], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVOktrrI&md5=5d00d73dda1fc0d8f0f07d12900282edIdentification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating CancerBurger, Matthew T.; Pecchi, Sabina; Wagman, Allan; Ni, Zhi-Jie; Knapp, Mark; Hendrickson, Thomas; Atallah, Gordana; Pfister, Keith; Zhang, Yanchen; Bartulis, Sarah; Frazier, Kelly; Ng, Simon; Smith, Aaron; Verhagen, Joelle; Haznedar, Joshua; Huh, Kay; Iwanowicz, Ed; Xin, Xiaohua; Menezes, Daniel; Merritt, Hanne; Lee, Isabelle; Wiesmann, Marion; Kaufman, Susan; Crawford, Kenneth; Chin, Michael; Bussiere, Dirksen; Shoemaker, Kevin; Zaror, Isabel; Maira, Sauveur-Michel; Voliva, Charles F.ACS Medicinal Chemistry Letters (2011), 2 (10), 774-779CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Phosphoinositide-3-kinases (PI3Ks) are important oncol. targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clin. trials for the treatment of cancer.
- 88Ihle, N. T.; Williams, R.; Chow, S.; Chew, W.; Berggren, M. I.; Paine-Murrieta, G.; Minion, D. J.; Halter, R. J.; Wipf, P.; Abraham, R.; Kirkpatrick, L.; Powis, G. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling Mol. Cancer Ther. 2004, 3, 763– 772[PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXls1anu7k%253D&md5=8c311288f085007b0f1b4846ea4aec37Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signalingIhle, Nathan T.; Williams, Ryan; Chow, Sherry; Chew, Wade; Berggren, Margareta I.; Paine-Murrieta, Gillian; Minion, Daniel J.; Halter, Robert J.; Wipf, Peter; Abraham, Robert; Kirkpatrick, Lynn; Powis, GarthMolecular Cancer Therapeutics (2004), 3 (7), 763-772CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)We have developed biol. stable semisynthetic viridins as inhibitors of phosphoinositide (PtdIns)-3-kinases. The most active compd. was PX-866, which inhibited purified PtdIns-3-kinase with an IC50 of 0.1 nmol/L and PtdIns-3-kinase signaling measured by phospho-Ser473-Akt levels in HT-29 colon cancer cells with an IC50 of 20 nmol/L. PX-866 administered to mice at 10 mg/kg inhibited phospho-Ser473-Akt in HT-29 colon tumor xenografts up to 80% with recovery taking >48 h after p.o. administration but more rapidly after i.v. or i.p. administration. PX-866 was eliminated from mouse plasma with a half-life of 18 min and a clearance of 360 mL/min/kg following i.v. administration and, when administered i.p. or p.o., showed first-pass metab. with sequential N-deallylation. Synthetic stds. of the N-deallylated metabolites of PX-866 inhibited PtdIns-3-kinase at low nanomolar per L concns. PX-866 exhibited in vivo antitumor activity against s.c. OvCar-3 human ovarian cancer and A-549 human lung cancer xenografts in immunodefficient mice with log cell kills up to 1.2. PX-866 also increased the antitumor activity of cisplatin against A-549 xenografts and radiation treatment against OvCar-3 xenografts. The results show that PX-866 is a biol. stable broad-spectrum PtdIns-3-kinase inhibitor with good pharmacokinetics that causes prolonged inhibition of PtdIns-3-kinase signaling in human tumor xenografts. PX-866 exhibits single agent in vivo antitumor activity and increases the antitumor effects of cisplatin and radiation treatment.
- 89Foster, P.; Yamaguchi, K.; Hsu, P. P.; Qian, F.; Du, X.; Wu, J.; Won, K. A.; Yu, P.; Jaeger, C. T.; Zhang, W.; Marlowe, C. K.; Keast, P.; Abulafia, W.; Chen, J.; Young, J.; Plonowski, A.; Yakes, F. M.; Chu, F.; Engell, K.; Bentzien, F.; Lam, S. T.; Dale, S.; Yturralde, O.; Matthews, D. J.; Lamb, P.; Laird, A. D. The selective PI3K inhibitor XL147 (SAR245408) inhibits tumor growth and survival and potentiates the activity of chemotherapeutic agents in preclinical models Mol. Cancer Ther. 2015, 14, 931– 940 DOI: 10.1158/1535-7163.MCT-14-0833[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmtlCit7o%253D&md5=3f20e5ab563c242807ddb021616d994eThe Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor ModelsFoster, Paul; Yamaguchi, Kyoko; Hsu, Pin P.; Qian, Fawn; Du, Xiangnan; Wu, Jianming; Won, Kwang-Ai; Yu, Peiwen; Jaeger, Christopher T.; Zhang, Wentao; Marlowe, Charles K.; Keast, Paul; Abulafia, Wendy; Chen, Jason; Young, Jenny; Plonowski, Artur; Yakes, F. Michael; Chu, Felix; Engell, Kelly; Bentzien, Frauke; Lam, Sanh T.; Dale, Stephanie; Yturralde, Olivia; Matthews, David J.; Lamb, Peter; Laird, A. DouglasMolecular Cancer Therapeutics (2015), 14 (4), 931-940CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently obsd. in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 h. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that obsd. with the corresponding single agents. Mol Cancer Ther; 14(4); 931-40. ©2015 AACR.
- 90Yu, P.; Laird, A. D.; Du, X.; Wu, J.; Won, K.; Yamaguchi, K.; Hsu, P. P.; Qian, F.; Jaeger, C. T.; Zhang, W.; Buhr, C. A.; Shen, P.; Abulafia, W.; Chen, J.; Young, J.; Plonowski, A.; Yakes, F. M.; Chu, F.; Lee, M.; Bentzien, F.; Lam, S. T.; Dale, S.; Matthews, D. J.; Lamb, P.; Foster, P. Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathway Mol. Cancer Ther. 2014, 13, 1078– 1091 DOI: 10.1158/1535-7163.MCT-13-0709[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnsFWjsLw%253D&md5=d300f7d62af36c9c9eeb6a5826e48eb2Characterization of the Activity of the PI3K/mTOR Inhibitor XL765 (SAR245409) in Tumor Models with Diverse Genetic Alterations Affecting the PI3K PathwayYu, Peiwen; Laird, A. Douglas; Du, Xiangnan; Wu, Jianming; Won, Kwang-Ai; Yamaguchi, Kyoko; Hsu, Pin Pin; Qian, Fawn; Jaeger, Christopher T.; Zhang, Wentao; Buhr, Chris A.; Shen, Paula; Abulafia, Wendy; Chen, Jason; Young, Jenny; Plonowski, Arthur; Yakes, F. Michael; Chu, Felix; Lee, Michelle; Bentzien, Frauke; Lam, Sanh Tan; Dale, Stephanie; Matthews, David J.; Lamb, Peter; Foster, PaulMolecular Cancer Therapeutics (2014), 13 (5), 1078-1091CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Activation of the PI3K (phosphoinositide 3-kinase) pathway is a frequent occurrence in human tumors and is thought to promote growth, survival, and resistance to diverse therapies. Here, we report pharmacol. characterization of the pyridopyrimidinone deriv. XL765 (SAR245409), a potent and highly selective pan inhibitor of class I PI3Ks (α, β, γ, and δ) with activity against mTOR. Broad kinase selectivity profiling of >130 protein kinases revealed that XL765 is highly selective for class I PI3Ks and mTOR over other kinases. In cellular assays, XL765 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL765 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approx. 24 h. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is assocd. with antiproliferative, antiangiogenic, and proapoptotic effects. Mol Cancer Ther; 13(5); 1078-91. ©2014 AACR.
- 91Lin, N. U. Targeted therapies in brain metastases Curr. Treat. Options Neurol. 2014, 16, 276 DOI: 10.1007/s11940-013-0276-z[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c3oslOrtQ%253D%253D&md5=ca3b1092fd955c72d4e54a9910dd65fbTargeted therapies in brain metastasesLin Nancy UCurrent treatment options in neurology (2014), 16 (1), 276 ISSN:1092-8480.OPINION STATEMENT: Brain metastases are a major clinical problem in patients with advanced breast cancer, lung cancer, melanoma, and renal cell carcinoma. Initial treatment for patients with brain metastases typically includes radiotherapy, either whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or both. Surgical resection is generally reserved for good prognosis patients with limited/controlled extracranial metastases and a single brain lesion. Once patients progress through upfront treatment, the treatment approach is quite variable and there is no clearly defined standard-of-care. Over the past decade, the role of systemic therapies and in particular, targeted therapies has been increasingly explored in patients with brain metastases from solid tumors. For example, lapatinib has been studied as monotherapy, and in combination with capecitabine, in patients with HER2-positive breast cancer, and activity has been observed in both the upfront and refractory settings. In patients with nonsmall cell lung cancer (NSCLC), central nervous system (CNS) activity has been reported with gefinitib and erlotinib. Finally, in melanoma, the B-raf inhibitors vemurafenib and dabrafenib, and the immunomodulator, ipilumimab, have reported CNS activity. Moving forward, the challenge will be to understand how to optimize the activity of targeted agents in the CNS and how to best incorporate them into the current treatment paradigms in order to improve outcomes for this patient population.
- 92Sutherlin, D. P.; Sampath, D.; Berry, M.; Castanedo, G.; Chang, Z.; Chuckowree, I.; Dotson, J.; Folkes, A.; Friedman, L.; Goldsmith, R.; Heffron, T.; Lee, L.; Lesnick, J.; Lewis, C.; Mathieu, S.; Nonomiya, J.; Olivero, A.; Pang, J.; Prior, W. W.; Salphati, L.; Sideris, S.; Tian, Q.; Tsui, V.; Wan, N. C.; Wang, S.; Wiesmann, C.; Wong, S.; Zhu, B.-Y. Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer J. Med. Chem. 2010, 53, 1086– 1097 DOI: 10.1021/jm901284w
- 93Folkes, A. J.; Ahmadi, K.; Alderton, W. K.; Alix, S.; Baker, S. J.; Box, G.; Chuckowree, I. S.; Clarke, P. A.; Depledge, P.; Eccles, S. A.; Friedman, L. S.; Hayes, A.; Hancox, T. C.; Kugendradas, A.; Lensun, L.; Moore, P.; Olivero, A. G.; Pang, J.; Patel, S.; Pergl-Wilson, G. H.; Raynaud, F. I.; Robson, A.; Saghir, N.; Salphati, L.; Sohal, S.; Ultsch, M. H.; Valenti, M.; Wallweber, H. J.; Wan, N. C.; Wiesmann, C.; Workman, P.; Zhyvoloup, A.; Zvelebil, M. J.; Shuttleworth, S. J. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer J. Med. Chem. 2008, 51, 5522– 5532 DOI: 10.1021/jm800295d[ACS Full Text], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVCmsr7E&md5=742084954685353ceaf18660ab3a0703The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancerFolkes, Adrian J.; Ahmadi, Khatereh; Alderton, Wendy K.; Alix, Sonia; Baker, Stewart J.; Box, Gary; Chuckowree, Irina S.; Clarke, Paul A.; Depledge, Paul; Eccles, Suzanne A.; Friedman, Lori S.; Hayes, Angela; Hancox, Timothy C.; Kugendradas, Arumugam; Lensun, Letitia; Moore, Pauline; Olivero, Alan G.; Pang, Jodie; Patel, Sonal; Pergl-Wilson, Giles H.; Raynaud, Florence I.; Robson, Anthony; Saghir, Nahid; Salphati, Laurent; Sohal, Sukhjit; Ultsch, Mark H.; Valenti, Melanie; Wallweber, Heidi J. A.; Wan, Nan Chi; Wiesmann, Christian; Workman, Paul; Zhyvoloup, Alexander; Zvelebil, Marketa J.; Shuttleworth, Stephen J.Journal of Medicinal Chemistry (2008), 51 (18), 5522-5532CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivs. were prepd. and evaluated as inhibitors of PI3 kinase p110α. The synthesis, biol. activity, and further profiling of these compds. are described. This work resulted in the discovery of GDC-0941 (I) which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clin. trials for the treatment of cancer.
- 94(a) Heffron, T. P.; Salphati, L.; Alicke, B.; Cheong, J.; Dotson, J.; Edgar, K.; Goldsmith, R.; Gould, S. E.; Lee, L. B.; Lesnick, J. D.; Lewis, C.; Ndubaku, C. O.; Nonomiya, J.; Olivero, A. G.; Pang, J.; Plise, E. G.; Sideris, S.; Trapp, S.; Wallin, J.; Wang, L.; Zhang, X. The design and identification of brain penetrant inhibitors of phosphoinositide 3-kinase a J. Med. Chem. 2012, 55, 8007– 8020 DOI: 10.1021/jm300867c(b) Salphati, L.; Heffron, T. P.; Alicke, B.; Nishimura, M.; Barck, K.; Carano, R. A.; Cheong, J.; Edgar, K.; Greve, J.; Kharbanda, S.; Koeppen, H.; Lau, S.; Lee, L. B.; Pang, J.; Plise, E. G.; Pokorny, J. L.; Reslan, H. B.; Sarkaria, J. N.; Wallin, J. J.; Zhang, X.; Gould, S. E.; Olivero, A. G.; Phillips, H. S. Targeting the PI3K pathway in the brain – efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier Clin. Cancer Res. 2012, 18, 6239– 6248 DOI: 10.1158/1078-0432.CCR-12-0720[Crossref], [PubMed], [CAS], Google Scholar94bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs12jur3J&md5=04450de4d9e3106d7f4d8fb831f9e9acTargeting the PI3K Pathway in the Brain-Efficacy of a PI3K Inhibitor Optimized to Cross the Blood-Brain BarrierSalphati, Laurent; Heffron, Timothy P.; Alicke, Bruno; Nishimura, Merry; Barck, Kai; Carano, Richard A.; Cheong, Jonathan; Edgar, Kyle A.; Greve, Joan; Kharbanda, Samir; Koeppen, Hartmut; Lau, Shari; Lee, Leslie B.; Pang, Jodie; Plise, Emile G.; Pokorny, Jenny L.; Reslan, Hani Bou; Sarkaria, Jann N.; Wallin, Jeffrey J.; Zhang, Xiaolin; Gould, Stephen E.; Olivero, Alan G.; Phillips, Heidi S.Clinical Cancer Research (2012), 18 (22), 6239-6248CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: Glioblastoma (GBM), the most common primary brain tumor in adults, presents a high frequency of alteration in the PI3K pathway. Our objectives were to identify a dual PI3K/mTOR inhibitor optimized to cross the blood-brain barrier (BBB) and characterize its brain penetration, pathway modulation in the brain and efficacy in orthotopic xenograft models of GBM. Exptl. Design: Physicochem. properties of PI3K inhibitors were optimized using in silico tools, leading to the identification of GNE-317. This compd. was tested in cells overexpressing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Following administration to mice, GNE-317 plasma and brain concns. were detd., and phosphorylated biomarkers (pAkt, p4EBP1, and pS6) were measured to assess PI3K pathway suppression in the brain. GNE-317 efficacy was evaluated in the U87, GS2, and GBM10 orthotopic models of GBM. Results: GNE-317 was identified as having physicochem. properties predictive of low efflux by P-gp and BCRP. Studies in transfected MDCK cells showed that GNE-317 was not a substrate of either transporter. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-h postdose. GNE-317 was efficacious in the U87, GS2, and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, resp. Conclusions: These results indicated that specific optimization of PI3K inhibitors to cross the BBB led to potent suppression of the PI3K pathway in healthy brain. The efficacy of GNE-317 in 3 intracranial models of GBM suggested that this compd. could be effective in the treatment of GBM. Clin Cancer Res; 18(22); 6239-48. ©2012 AACR.
- 95Maira, M.; Schnell, C.; Lollini, P.; Chouaid, C.; Schmid, P.; Nanni, P.; Lam, D.; Di Tomaso, E.; C. Massacesi, C.; Rodon, J. Preclinical and preliminary clinical activity of NVP-BKM-120, an oral pan-class I PI3K inhibitor, in the brain Ann. Oncol. 2012, 23 (Suppl.) 1675
- 96Wen, P. Y.; Yung, W. K. A.; Mellinghoff, I. K.; Ramkissoon, S.; Alexander, B. M.; Rinne, M. L.; Colman, H.; Omuro, A. M. P.; DeAngelis, L. M.; Gilbert, M. R.; De Groot, J. F.; Cloughesy, T. F.; Chi, A. S.; Lee, E. Q.; Nayak, L.; Betchelor, T.; Chang, S. M.; Prados, M.; Reardon, D. A.; Ligon, K. Phase II trial of the phosphatidylinositol-3 kinase (PI3K) inhibitor buparlisib (BKM120) in recurrent glioblastoma J. Clin. Oncol. 2014, 32 (Suppl.) 2019
- 97Cmiljanovic, V.; Cmiljanovic, N.; Marone, R.; Beaufils, F.; Zhang, X.; Zvelebil, M.; Hebeisen, P.; Lang, M.; Mestan, J.; Melone, A.; Bohnacker, T.; Gaudio, E.; Tarantelli, C.; Bertoni, F.; Ritschard, R.; Pretre, V.; Wicki, A.; Fabbro, D.; Hillmann, P.; Williams, R.; Giese, B.; Wymann, M. P. Abstract 2664: PQR309: structure-based design, synthesis and biological evaluation of a novel, selective, dual pan-PI3K/mTOR inhibitor Cancer Res. 2015, 75 (Suppl.) 2664 DOI: 10.1158/1538-7445.AM2015-2664
- 98Cmiljanovic, V.; Ettlin, R. A.; Beaufils, F.; Dieterle, W.; Hillmann, P.; Mestan, J.; Melone, A.; Bohnacker, T.; Lang, M.; Cmiljanovic, N.; Giese, B.; Hebeisen, P.; Wymann, M. P.; Fabbro, D. Abstract 4514: PQR309: A potent, brain-penetrant, dual pan-PI3K/mTOR inhibitor with excellent oral bioavailability and tolerability Cancer Res. 2015, 75 (Suppl.) 4514 DOI: 10.1158/1538-7445.AM2015-4514
- 99Lannutti, B. J.; Meadows, S. A.; Herman, S. E. M.; Kashishian, A.; Steiner, B.; Johnson, A. J.; Byrd, J. C.; Tyner, J. W.; Loriaux, M. M.; Deininger, M.; Druker, B. J.; Puri, K. D.; Ulrich, R. G.; Giese, N. A. CAL-101, a p100d selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability Blood 2011, 117, 591– 594 DOI: 10.1182/blood-2010-03-275305
- 100Janssens, A. Ibrutinib and idelalisib, the B-cell receptor antagonists available for use in daily clinical practice Belg. J. Hematol. 2015, 6, 216– 224
- 101Highlights of Prescribing Information. Zydelig. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205858lbl.pdf (accessed June 12, 2016) .
- 102Benjamin, D.; Colombi, M.; Moroni, C.; Hall, M. H. Rapamycin passes the torch: a new generation of mTOR inhibitors Nat. Rev. Drug Discovery 2011, 10, 868– 880 DOI: 10.1038/nrd3531[Crossref], [PubMed], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlyis7vI&md5=a909649a82f3a2ce11c6b8fee78fa69eRapamycin passes the torch: a new generation of mTOR inhibitorsBenjamin, Don; Colombi, Marco; Moroni, Christoph; Hall, Michael N.Nature Reviews Drug Discovery (2011), 10 (11), 868-880CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Mammalian target of rapamycin (mTOR) is an atypical protein kinase that controls growth and metab. in response to nutrients, growth factors and cellular energy levels, and it is frequently dysregulated in cancer and metabolic disorders. Rapamycin is an allosteric inhibitor of mTOR, and was approved as an immuno-suppressant in 1999. In recent years, interest has focused on its potential as an anticancer drug. However, the performance of rapamycin and its analogs (rapalogues) has been undistinguished despite isolated successes in subsets of cancer, suggesting that the full therapeutic potential of targeting mTOR has yet to be exploited. A new generation of ATP-competitive inhibitors that directly target the mTOR catalytic site display potent and comprehensive mTOR inhibition and are in early clin. trials.
- 103Crowe, A.; Lemaire, M. In vitro and in situ absorption of SDZ-RAD using a human intestinal cell line (Caco-2) and a single pass perfusion model in rats: comparison with rapamycin Pharm. Res. 1998, 15, 1666– 1672 DOI: 10.1023/A:1011940108365
- 104Pike, K. G.; Malagu, K.; Hummersone, M. G.; Menear, K. A.; Duggan, H. M.; Gomez, S.; Martin, N. M.; Ruston, L.; Pass, S. L.; Pass, M. Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014 Bioorg. Med. Chem. Lett. 2013, 23, 1212– 1216 DOI: 10.1016/j.bmcl.2013.01.019[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFajs7c%253D&md5=325cb45f84bb4357005315ab3b27c0aaOptimization of potent and selective dual mTORC1 and mTORC2 inhibitors: The discovery of AZD8055 and AZD2014Pike, Kurt G.; Malagu, Karine; Hummersone, Marc G.; Menear, Keith A.; Duggan, Heather M. E.; Gomez, Sylvie; Martin, Niall M. B.; Ruston, Linette; Pass, Sarah L.; Pass, MartinBioorganic & Medicinal Chemistry Letters (2013), 23 (5), 1212-1216CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency while maintaining or improving other key parameters, such as aq. soly. and margins over hERG IC50, led to the discovery of the clin. candidate AZD8055. Further optimization, particularly aimed at reducing the rate of metab. in human hepatocyte incubations, resulted in the discovery of the clin. candidate AZD2014.
- 105Mortensen, D. S.; Perrin-Ninkovic, S. M.; Shevlin, G.; Zhao, J.; Packard, G.; Bahmanyar, S.; Correa, M.; Elsner, J.; Harris, R.; Lee, B. G. S.; Papa, P.; Parnes, J. S.; Riggs, J. R.; Sapienza, J.; Tehrani, L.; Whitefield, B.; Apuy, J.; Bisonette, R. R.; Gamez, J. C.; Hickman, M.; Khambatta, G.; Leisten, J.; Peng, S. X.; Richardson, S. J.; Cathers, B. E.; Canan, S. S.; Moghaddam, M. F.; Raymon, H. K.; Worland, P.; Narla, R. K.; Fultz, K. E.; Sankar, S. Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223 J. Med. Chem. 2015, 58, 5323– 5333 DOI: 10.1021/acs.jmedchem.5b00626[ACS Full Text], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVansrzI&md5=0f1ed6d929618ea8468fefefb196c606Discovery of Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor CC-223Mortensen, Deborah S.; Perrin-Ninkovic, Sophie M.; Shevlin, Graziella; Zhao, Jingjing; Packard, Garrick; Bahmanyar, Sogole; Correa, Matthew; Elsner, Jan; Harris, Roy; Lee, Branden G. S.; Papa, Patrick; Parnes, Jason S.; Riggs, Jennifer R.; Sapienza, John; Tehrani, Lida; Whitefield, Brandon; Apuy, Julius; Bisonette, Rene R.; Gamez, James C.; Hickman, Matt; Khambatta, Godrej; Leisten, Jim; Peng, Sophie X.; Richardson, Samantha J.; Cathers, Brian E.; Canan, Stacie S.; Moghaddam, Mehran F.; Raymon, Heather K.; Worland, Peter; Narla, Rama Krishna; Fultz, Kimberly E.; Sankar, SabitaJournal of Medicinal Chemistry (2015), 58 (13), 5323-5333CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compds. with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223, I, for clin. development.
- 106https://clinicaltrials.gov/ct2/show/NCT02619864 (accessed June 12, 2016) .
- 107Varga, A.; Mita, M. M.; Wu, J. J.; Nemunaitis, J. J.; Cloughesy, T. F.; Mischel, P. S.; Bendell, J. C.; Shih, K. C.; Paz-Ares, L. G.; Mahipal, A.; Delord, J.-P.; Kelley, R. K.; Soria, J.-C.; Wong, L.; Xu, S.; James, A.; Wu, X.; Chopra, R.; Hege, K.; Muster, P. N. Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid tumors J. Clin. Oncol. 2013, 31 (Suppl.) 2606
- 108Basu, B.; Dean, E.; Puglisi, M.; Greystoke, A.; Ong, M.; Burke, W.; Cavallin, M.; Bigley, G.; Womack, C.; Harrington, E. A.; Green, S.; Oelmann, E.; de Bono, J. S.; Ranson, M.; Banerji, U. First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor AZD2014 Clin. Cancer Res. 2015, 21, 3412– 3419 DOI: 10.1158/1078-0432.CCR-14-2422[Crossref], [PubMed], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1yqtrnN&md5=f5d4552e713519b1276135d56dbaf020First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014Basu, Bristi; Dean, Emma; Puglisi, Martina; Greystoke, Alastair; Ong, Michael; Burke, Wendy; Cavallin, Maria; Bigley, Graham; Womack, Christopher; Harrington, Elizabeth A.; Green, Stephen; Oelmann, Elisabeth; de Bono, Johann S.; Ranson, Malcolm; Banerji, UdaiClinical Cancer Research (2015), 21 (15), 3412-3419CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: AZD2014 is a novel, oral, m-TORC 1/2 inhibitor that has shown in vitro and in vivo efficacy across a range of preclin. human cancer models. Exptl. Design: A rolling six-dose escalation was performed to define an MTD (part A), and at MTD a further cohort of patients was treated to further characterize toxicities and perform pre- and posttreatment biopsies (part B). AZD2014 was administered orally twice a day continuously. Flow cytometry, ELISA, and immunohistochem. were used to quantify pharmacodynamic biomarkers. Pharmacokinetic anal. was carried out by mass spectrometry. Results: A total of 56 patients were treated across a dose range of 25 to 100 mg. The MTD was 50 mg twice daily. The dose-limiting toxicities were fatigue and mucositis. At the MTD, the most common adverse events (AE) were fatigue (78%), nausea (51%), and mucositis (49%), but these were equal to or greater than grade 3 in only 5% of patients. Drug levels achieved at the MTD (AUCss 6686 ng·h/mL, Cmax ss 1,664 ng/mL) were consistent with activity in preclin. models. A redn. in p-S6 levels and Ki67 staining was obsd. in 8 of 8 and 5 of 9 evaluable paired biopsy samples. Partial responses were seen in a patient with pancreatic cancer and a patient with breast cancer, who were found to have a PDGFR and ERBB2 mutation, resp. Conclusions: The recommended phase II dose for further evaluation of AZD2014 is 50 mg twice daily, and at this dose it has been possible to demonstrate pharmacol. relevant plasma concns., target inhibition in tumor, and clin. responses. Clin Cancer Res; 21(15); 3412-9. ©2015 AACR.
- 109Lin, F.; Buil, L.; Sherris, D.; Beijnen, J. H.; van Tellingen, O. Dual mTORC1 and mTORC2 inhibitor Palmoid 529 penetrates the blood-brain barrier without restriction by ABCB1 and ABCG2 Int. J. Cancer 2013, 133, 1222– 1234 DOI: 10.1002/ijc.28126[Crossref], [PubMed], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltVCjsb0%253D&md5=1f8450a5a09cf68eabd2b16227e1518bDual mTORC1 and mTORC2 inhibitor Palomid 529 penetrates the Blood-Brain Barrier without restriction by ABCB1 and ABCG2Lin, Fan; Buil, Levi; Sherris, David; Beijnen, Jos H.; Tellingen, OlafInternational Journal of Cancer (2013), 133 (5), 1222-1233CODEN: IJCNAW; ISSN:0020-7136. (John Wiley & Sons, Inc.)Palomid 529, a novel dual mTORC1/2 inhibitor has displayed interesting activities in exptl. models and is a candidate for clin. evaluation. We have assessed the interaction of Palomid 529 with ATP-binding cassette (ABC) drug efflux transporters ABCB1 (P-gp/P-glycoprotein) and ABCG2 (BCRP/Breast Cancer Resistant Protein) by in vitro transwell assays, and their effects on the brain penetration using drug disposition anal. of i.v. and oral Palomid 529 in wild-type (WT) and Abcb1 and/or Abcg2 knockout (KO) mice. Palomid 529 lacked affinity for these transporters in vitro, in contrast to GDC-0941, a small mol. PI3K inhibitor, which we used as control substance for in vitro transport. The plasma AUCi.v. of micronized and DMSO formulated Palomid 529 was similar in WT and KO mice. Importantly, the brain and brain tumor concn. of Palomid 529 at a high dose (54 mg/kg) was also similar in both strains, whereas a less than 1.4-fold difference (p < 0.05) was found at the low (5.4 mg/kg) dose. Because of poor soly., the oral bioavailability of micronized Palomid 529 was only 5%. Olive oil or spray-dried formulation greatly improved the bioavailability up to 50%. Finally, Palomid 529 effectively inhibits the orthotopic U87 glioblastoma growth. In summary, Palomid 529 is the first mTOR targeting drug lacking affinity for ABCB1/ABCG2 and having good brain penetration. This warrants further evaluation of Palomid 529 for treatment of high-grade gliomas and other intracranial malignancies.
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For AKT inhibitors that have entered clinical studies see the following:
(a) Pal, S. K.; Reckamp, K.; Yu, H.; Figlin, R. A. Akt inhibitors in clinical development for the treatment of cancer Expert Opin. Invest. Drugs 2010, 19, 1355– 1366 DOI: 10.1517/13543784.2010.520701(b) Rodon, J.; Dienstmann, R.; Serra, V.; Tabernero, J. Development of PI3K inhibitors: lessons learned from early clinical trials Nat. Rev. Clin. Oncol. 2013, 10, 143– 153 DOI: 10.1038/nrclinonc.2013.10[Crossref], [PubMed], [CAS], Google Scholar110bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsFGgs7w%253D&md5=cc6ef16605ed3f5f8619d6a1c7894d5cDevelopment of PI3K inhibitors: lessons learned from early clinical trialsRodon, Jordi; Dienstmann, Rodrigo; Serra, Violeta; Tabernero, JosepNature Reviews Clinical Oncology (2013), 10 (3), 143-153CODEN: NRCOAA; ISSN:1759-4774. (Nature Publishing Group)A review. The phosphatidylinositol 3-kinase (PI3K) pathway has an important role in cell metab., growth, migration, survival and angiogenesis. Drug development aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway has been fomented by observations that alterations in this pathway induce tumor formation and that inappropriate PI3K signalling is a frequent occurrence in human cancer. Many of the agents developed have been evaluated in early stage clin. trials. This Review focuses on early clin. and translational data related to inhibitors of the PI3K/AKT/mTOR pathway, as these data will likely guide the further clin. development of such agents. We review data from those trials, delineating the safety profile of the agents-whether obsd. sequelae could be mechanism-based or off-target effects-and drug efficacy. We describe predictive biomarkers explored in clin. trials and preclin. mechanisms of resistance. We also discuss key unresolved translational questions related to the clin. development of inhibitors of the PI3K/AKT/mTOR pathway and propose designs for biomarker-driven trials to address those issues. - 111Hilgard, P.; Klenner, T.; Stekar, J.; Nossner, G.; Kutscher, B.; Engel, J. D-21266, a new heterocyclic alkylphospholipid with antitumor activity Eur. J. Cancer 1997, 33, 442– 446 DOI: 10.1016/S0959-8049(97)89020-X
- 112Hirai, H.; Sootome, H.; Nakatsuru, Y.; Miyama, K.; Taguchi, S.; Tsujioka, K.; Ueno, Y.; Hatch, H.; Majumder, P. K.; Pan, B. S.; Kotani, H. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo Mol. Cancer Ther. 2010, 9, 1956– 1967 DOI: 10.1158/1535-7163.MCT-09-1012[Crossref], [PubMed], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFertbnL&md5=f2d97ab64963cc82d97b35697e49b172MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivoHirai, Hiroshi; Sootome, Hiroshi; Nakatsuru, Yoko; Miyama, Katsuyoshi; Taguchi, Shunsuke; Tsujioka, Kyoko; Ueno, Yoko; Hatch, Harold; Majumder, Pradip K.; Pan, Bo-Sheng; Kotani, HidehitoMolecular Cancer Therapeutics (2010), 9 (7), 1956-1967CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)The serine/threonine kinase Akt lies at a crit. signaling node downstream of phosphatidylinositol-3-kinase and is important in promoting cell survival and inhibiting apoptosis. An Akt inhibitor may be particularly useful for cancers in which increased Akt signaling is assocd. with reduced sensitivity to cytotoxic agents or receptor tyrosine kinase inhibitors. We evaluated the effect of a novel allosteric Akt inhibitor, MK-2206, in combination with several anticancer agents. In vitro, MK-2206 synergistically inhibited cell proliferation of human cancer cell lines in combination with mol. targeted agents such as erlotinib (an epidermal growth factor receptor inhibitor) or lapatinib (a dual epidermal growth factor receptor/human epidermal growth factor receptor 2 inhibitor). Complementary inhibition of erlotinib-insensitive Akt phosphorylation by MK-2206 was one mechanism of synergism, and a synergistic effect was found even in erlotinib-insensitive cell lines. MK-2206 also showed synergistic responses in combination with cytotoxic agents such as topoisomerase inhibitors (doxorubicin, camptothecin), antimetabolites (gemcitabine, 5-fluorouracil), anti-microtubule agents (docetaxel), and DNA cross-linkers (carboplatin) in lung NCI-H460 or ovarian A2780 tumor cells. The synergy with docetaxel depended on the treatment sequence; a schedule of MK-2206 dosed before docetaxel was not effective. MK-2206 suppressed the Akt phosphorylation that is induced by carboplatin and gemcitabine. In vivo, MK-2206 in combination with these agents exerted significantly more potent tumor inhibitory activities than each agent in the monotherapy setting. These findings suggest that Akt inhibition may augment the efficacy of existing cancer therapeutics; thus, MK-2206 is a promising agent to treat cancer patients who receive these cytotoxic and/or mol. targeted agents.
- 113Dunn, D. E.; He, D. N.; Yang, P.; Johansen, M.; Newman, R. A.; Lo, D. C. In vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke models J. Neurochem. 2011, 119, 805– 814 DOI: 10.1111/j.1471-4159.2011.07439.x[Crossref], [PubMed], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVGqsrrP&md5=6f77667e0bf5962040c6ecac0ffd5f7bIn vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke modelsDunn, Denise E.; He, Dong Ning; Yang, Peiying; Johansen, Mary; Newman, Robert A.; Lo, Donald C.Journal of Neurochemistry (2011), 119 (3 & 4), 805-814CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)The principal active constituent of the botanical drug candidate PBI-05204, a supercrit. CO2 ext. of Nerium oleander, is the cardiac glycoside oleandrin. PBI-05204 shows potent anticancer activity and is currently in phase I clin. trial as a treatment for patients with solid tumors. We have previously shown that neriifolin, which is structurally related to oleandrin, provides robust neuroprotection in brain slice and whole animal models of ischemic injury. However, neriifolin itself is not a suitable drug development candidate and the FDA-approved cardiac glycoside digoxin does not cross the blood-brain barrier. We report here that both oleandrin as well as the full PBI-05204 ext. can also provide significant neuroprotection to neural tissues damaged by oxygen and glucose deprivation as occurs in ischemic stroke. Critically, we show that the neuroprotective activity of PBI-05204 is maintained for several hours of delay of administration after oxygen and glucose deprivation treatment. We provide evidence that the neuroprotective activity of PBI-05204 is mediated through oleandrin and/or other cardiac glycoside constituents, but that addnl., non-cardiac glycoside components of PBI-05204 may also contribute to the obsd. neuroprotective activity. Finally, we show directly that both oleandrin and the protective activity of PBI-05204 are blood brain barrier penetrant in a novel model for in vivo neuroprotection. Together, these findings suggest clin. potential for PBI-05204 in the treatment of ischemic stroke and prevention of assocd. neuronal death.
- 114Heerding, D. A.; Rhodes, N.; Leber, J. D.; Clark, T. J.; Keenan, R. M.; Lafrance, L. V.; Li, M.; Safonov, I. G.; Takata, D. T.; Venslavsky, J. W.; Yamashita, D. S.; Choudhry, A. E.; Copeland, R. A.; Lai, Z.; Schaber, M. D.; Tummino, P. J.; Strum, S. L.; Wood, E. R.; Duckett, D. R.; Eberwein, D.; Knick, V. B.; Lansing, T. J.; McConnell, R. T.; Zhang, S.; Minthorn, E. A.; Concha, N. O.; Warren, G. L.; Kumar, R. Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase J. Med. Chem. 2008, 51, 5663– 5679 DOI: 10.1021/jm8004527[ACS Full Text], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVChs7bE&md5=c0e6f283a3ee79dffafdd90ec69513bcIdentification of 4-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a Novel Inhibitor of AKT KinaseHeerding, Dirk A.; Rhodes, Nelson; Leber, Jack D.; Clark, Tammy J.; Keenan, Richard M.; Lafrance, Louis V.; Li, Mei; Safonov, Igor G.; Takata, Dennis T.; Venslavsky, Joseph W.; Yamashita, Dennis S.; Choudhry, Anthony E.; Copeland, Robert A.; Lai, Zhihong; Schaber, Michael D.; Tummino, Peter J.; Strum, Susan L.; Wood, Edgar R.; Duckett, Derek R.; Eberwein, Derek; Knick, Victoria B.; Lansing, Timothy J.; McConnell, Randy T.; Zhang, Shu Yun; Minthorn, Elisabeth A.; Concha, Nestor O.; Warren, Gregory L.; Kumar, RakeshJournal of Medicinal Chemistry (2008), 51 (18), 5663-5679CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant neg. AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compd. 3g (GSK690693, I). Compd. 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC50 values of 2, 13, and 9 nM against AKT1, 2, and 3, resp. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compd. 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3β. I.p. administration of 3g in immunocompromised mice results in the inhibition of GSK3β phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.
- 115Dumble, M.; Crouthamel, M.; Zhang, S.; Schaber, M.; Levy, D.; Robell, K.; Liu, Q.; Figueroa, D. J.; Minthorn, E. A.; Seefeld, M. A.; Rouse, M. B.; Rabindran, S. K.; Heerding, D. A.; Kumar, R. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor PLoS One 2014, 9, e100880 DOI: 10.1371/journal.pone.0100880[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1emur3K&md5=893494388f4f390ae5a6bc3d30114c89Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitorDumble, Melissa; Crouthamel, Ming-Chih; Zhang, Shu-Yun; Schaber, Michael; Levy, Dana; Robell, Kimberly; Liu, Qi; Figueroa, David J.; Minthorn, Elisabeth A.; Seefeld, Mark A.; Rouse, Meagan B.; Rabindran, Sridhar K.; Heerding, Dirk A.; Kumar, RakeshPLoS One (2014), 9 (6), e100880/1-e100880/11, 11 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clin. studies. Both compds. are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compd. show decreased phosphorylation of several substrates downstream of AKT. Both compds. have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histol. origins. Improved kinase selectivity was assocd. with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater redn. in phospho-S6 levels. Taken together these results support clin. evaluation of the AKT inhibitors in cancer, esp. in combination with MEK inhibitor.
- 116Blake, J. F.; Xu, R.; Bencsik, J. R.; Xiao, D.; Kallan, N. C.; Schlachter, S.; Mitchell, I. S.; Spencer, K. L.; Banka, A. L.; Wallace, E. M.; Gloor, S. L.; Martinson, M.; Woessner, R. D.; Vigers, G. P.; Brandhuber, B. J.; Liang, J.; Safina, B. S.; Li, J.; Zhang, B.; Chabot, C.; Do, S.; Lee, L.; Oeh, J.; Sampath, D.; Lee, B. B.; Lin, K.; Liederer, B. M.; Skelton, N. J. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors J. Med. Chem. 2012, 55, 8110– 8127 DOI: 10.1021/jm301024w[ACS Full Text], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1yrtr7K&md5=1fa690cda22a2548eb2795305e1c7253Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human TumorsBlake, James F.; Xu, Rui; Bencsik, Josef R.; Xiao, Dengming; Kallan, Nicholas C.; Schlachter, Stephen; Mitchell, Ian S.; Spencer, Keith L.; Banka, Anna L.; Wallace, Eli M.; Gloor, Susan L.; Martinson, Matthew; Woessner, Richard D.; Vigers, Guy P. A.; Brandhuber, Barbara J.; Liang, Jun; Safina, Brian S.; Li, Jun; Zhang, Birong; Chabot, Christine; Do, Steven; Lee, Leslie; Oeh, Jason; Sampath, Deepak; Lee, Brian B.; Lin, Kui; Liederer, Bianca M.; Skelton, Nicholas J.Journal of Medicinal Chemistry (2012), 55 (18), 8110-8127CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compds. that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compds. demonstrate potent inhibition of all three Akt isoforms in biochem. assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biol. studies with one such compd., 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clin. trials for the treatment of cancer.
- 117Lapierre, J.-M.; Eathiraj, S.; Vensel, D.; Liu, Y.; Bull, C. O.; Cornell-Kennon, S.; Iimura, S.; Kelleher, E. W.; Kizer, D. E.; Koerner, S.; Makhija, S.; Matsuda, A.; Moussa, M.; Namdev, N.; Savage, R. E.; Szwaya, J.; Volckova, E.; Westlund, N.; Wu, H.; Schwartz, B. Discovery of 3-(3-(4-(1-aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): an orally bioavailable, selective, and potent allosteric AKT inhibitor J. Med. Chem. 2016, 59, 6455– 6469 DOI: 10.1021/acs.jmedchem.6b00619[ACS Full Text], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpvFygtrg%253D&md5=fb29dbafd5fdd28e0e500f57e42cd42dDiscovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT InhibitorLapierre, Jean-Marc; Eathiraj, Sudharshan; Vensel, David; Liu, Yanbin; Bull, Cathy O.; Cornell-Kennon, Susan; Iimura, Shin; Kelleher, Eugene W.; Kizer, Darin E.; Koerner, Steffi; Makhija, Sapna; Matsuda, Akihisa; Moussa, Magdi; Namdev, Nivedita; Savage, Ronald E.; Szwaya, Jeff; Volckova, Erika; Westlund, Neil; Wu, Hui; Schwartz, BrianJournal of Medicinal Chemistry (2016), 59 (13), 6455-6469CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chem. series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compd. 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chem. class and the role of the cyclobutylamine moiety. Compd. 21a demonstrated high enzymic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compd. 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.
- 118Vink, S. R.; Schellens, J. H.; van Blitterswijk, W. J.; Verheij, M. Tumor and normal tissue pharmacokinetics of perifosine, an oral anti-cancer alkylphospholipid Invest. New Drugs 2005, 23, 279– 286 DOI: 10.1007/s10637-005-1436-0
- 119Dunn, D. E.; He, D. N.; Yang, P.; Johansen, M.; Newman, R. A.; Lo, D. C. In vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke models J. Neurochem. 2011, 119, 805– 814 DOI: 10.1111/j.1471-4159.2011.07439.x[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVGqsrrP&md5=6f77667e0bf5962040c6ecac0ffd5f7bIn vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke modelsDunn, Denise E.; He, Dong Ning; Yang, Peiying; Johansen, Mary; Newman, Robert A.; Lo, Donald C.Journal of Neurochemistry (2011), 119 (3 & 4), 805-814CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)The principal active constituent of the botanical drug candidate PBI-05204, a supercrit. CO2 ext. of Nerium oleander, is the cardiac glycoside oleandrin. PBI-05204 shows potent anticancer activity and is currently in phase I clin. trial as a treatment for patients with solid tumors. We have previously shown that neriifolin, which is structurally related to oleandrin, provides robust neuroprotection in brain slice and whole animal models of ischemic injury. However, neriifolin itself is not a suitable drug development candidate and the FDA-approved cardiac glycoside digoxin does not cross the blood-brain barrier. We report here that both oleandrin as well as the full PBI-05204 ext. can also provide significant neuroprotection to neural tissues damaged by oxygen and glucose deprivation as occurs in ischemic stroke. Critically, we show that the neuroprotective activity of PBI-05204 is maintained for several hours of delay of administration after oxygen and glucose deprivation treatment. We provide evidence that the neuroprotective activity of PBI-05204 is mediated through oleandrin and/or other cardiac glycoside constituents, but that addnl., non-cardiac glycoside components of PBI-05204 may also contribute to the obsd. neuroprotective activity. Finally, we show directly that both oleandrin and the protective activity of PBI-05204 are blood brain barrier penetrant in a novel model for in vivo neuroprotection. Together, these findings suggest clin. potential for PBI-05204 in the treatment of ischemic stroke and prevention of assocd. neuronal death.
- 120Newton, H. B. Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors Expert Rev. Anticancer Ther. 2003, 3, 595– 614 DOI: 10.1586/14737140.3.5.595[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpt1arsLc%253D&md5=313ecd065623c60f3dab2c2cb3ec91a6Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: growth factor and Ras signaling pathwaysNewton, Herbert B.Expert Review of Anticancer Therapy (2003), 3 (5), 595-614CODEN: ERATBJ; ISSN:1473-7140. (Future Drugs Ltd.)A review. Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Mol. neuro-oncol. has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that may be amenable to targeted therapy. Growth factor signaling pathways are often upregulated in brain tumors and may contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the Ras signaling pathway, which is frequently aberrant in brain tumors. Receptor tyrosine kinase inhibitors, antireceptor monoclonal antibodies and antisense oligonucleotides are targeted approaches under investigation as methods to regulate aberrant growth factor signaling pathways in brain tumors. Several receptor tyrosine kinase inhibitors, including imatinib mesylate (Gleevec), gefitinib (Iressa) and erlotinib (Tarceva), have entered clin. trials for high-grade glioma patients. Farnesyl transferase inhibitors, such as tipifarnib (Zarnestra), which impair processing of proRas and inhibit the Ras signaling pathway, have also entered clin. trials for patients with malignant gliomas. Further development of targeted therapies and evaluation of these new agents in clin. trials will be needed to improve survival and quality of life of patients with brain tumors.
- 121Singh, D.; Chan, J. M.; Zoppoli, P.; Niola, F.; Sullivan, R.; Castano, A.; Liu, E. M.; Reichel, J.; Porrati, P.; Pellegatta, S.; Qiu, K.; Gao, Z.; Ceccarelli, M.; Riccardi, R.; Brat, D. J.; Guha, A.; Aldape, K.; Golfinos, J. G.; Zagzag, D.; Mikkelsen, T.; Finocchiaro, G.; Lasorella, A.; Rabadan, R.; Iavarone, A. Transofrming fusions of FGFR and TACC genes in human glioblastoma Science 2012, 337, 1231– 1235 DOI: 10.1126/science.1220834
- 122(a) Shaw, A. T.; Hsu, P. P.; Awad, M. M.; Engleman, J. A. Tyrosine kinase gene rearrangements in epithelial malignancies Nat. Rev. Cancer 2013, 13, 772– 787 DOI: 10.1038/nrc3612[Crossref], [PubMed], [CAS], Google Scholar122ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1ertrjE&md5=ffb14b30706c8d935392647900b2e8c9Tyrosine kinase gene rearrangements in epithelial malignanciesShaw, Alice T.; Hsu, Peggy P.; Awad, Mark M.; Engelman, Jeffrey A.Nature Reviews Cancer (2013), 13 (11), 772-787CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. Chromosomal rearrangements that lead to oncogenic kinase activation are obsd. in many epithelial cancers. These cancers express activated fusion kinases that drive the initiation and progression of malignancy, and often have a considerable response to small-mol. kinase inhibitors, which validates these fusion kinases as 'druggable' targets. In this Review, we examine the etiol., pathogenic and clin. features that are assocd. with cancers harbouring oncogenic fusion kinases, including anaplastic lymphoma kinase (ALK), ROS1 and RET. We discuss the clin. outcomes with targeted therapies and explore strategies to discover addnl. kinases that are activated by chromosomal rearrangements in solid tumors.(b) Dieci, M. V.; Arnedos, M.; Andre, F.; Soria, J. C. Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives Cancer Discovery 2013, 3, 264– 279 DOI: 10.1158/2159-8290.CD-12-0362[Crossref], [PubMed], [CAS], Google Scholar122bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltVOktL4%253D&md5=0e694a7641aa83c1540f745576f04bfaFibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical PerspectivesDieci, Maria Vittoria; Arnedos, Monica; Andre, Fabrice; Soria, Jean CharlesCancer Discovery (2013), 3 (3), 264-279CODEN: CDAIB2; ISSN:2159-8274. (American Association for Cancer Research)A review. The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiol. processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifications, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, class-specific toxicity profiles and correctly designing clin. trials to address these different issues. Significance: FGF/FGFR pathway deregulations are increasingly recognized across different human cancers. Understanding the mechanisms at the basis of these alterations and their multiple roles in cancer promotion and drug resistance is a fundamental step for further implementation of targeted therapies and research strategies.
- 123Brooks, A. N.; Kilgour, E.; Smith, P. D. Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer Clin. Cancer Res. 2012, 18, 1855– 1862 DOI: 10.1158/1078-0432.CCR-11-0699[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkvFOmurk%253D&md5=a355aee7dc1b310177c6165b43896b75Molecular Pathways: Fibroblast Growth Factor Signaling: A New Therapeutic Opportunity in CancerBrooks, A. Nigel; Kilgour, Elaine; Smith, Paul D.Clinical Cancer Research (2012), 18 (7), 1855-1862CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)A review. The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling axis plays an important role in normal organ, vascular, and skeletal development. Deregulation of FGFR signaling through genetic modification or overexpression of the receptors (or their ligands) has been obsd. in numerous tumor settings, whereas the FGF/FGFR axis also plays a key role in driving tumor angiogenesis. A growing body of preclin. data shows that inhibition of FGFR signaling can result in antiproliferative and/or proapoptotic effects, both in vitro and in vivo, thus confirming the validity of the FGF/FGFR axis as a potential therapeutic target. In the past, development of therapeutic approaches to target this axis has been hampered by our inability to develop FGFR-selective agents. With the advent of a no. of new modalities for selectively inhibiting FGF/FGFR signaling, we are now in a unique position to test and validate clin. the many hypotheses that have been generated preclinically. Clin Cancer Res; 18(7); 1855-62.
- 124Gavine, P. R.; Mooney, L.; Kilgour, E.; Thomas, A. P.; Al-Kadhimi, K.; Beck, S.; Rooney, C.; Coleman, T.; Baker, D.; Mellor, M. J.; Brooks, A. N.; Klinowska, T. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family Cancer Res. 2012, 72, 2045– 2056 DOI: 10.1158/0008-5472.CAN-11-3034[Crossref], [PubMed], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xls1Wgsrs%253D&md5=cba90ad8f9b9e51cd10288868bbcc85eAZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase FamilyGavine, Paul R.; Mooney, Lorraine; Kilgour, Elaine; Thomas, Andrew P.; Al-Kadhimi, Katherine; Beck, Sarah; Rooney, Claire; Coleman, Tanya; Baker, Dawn; Mellor, Martine J.; Brooks, A. Nigel; Klinowska, TeresaCancer Research (2012), 72 (8), 2045-2056CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The fibroblast growth factor (FGF) signaling axis is increasingly implicated in tumorigenesis and chemoresistance. Several small-mol. FGF receptor (FGFR) kinase inhibitors are currently in clin. development; however, the predominant activity of the most advanced of these agents is against the kinase insert domain receptor (KDR), which compromises the FGFR selectivity. Here, we report the pharmacol. profile of AZD4547, a novel and selective inhibitor of the FGFR1, 2, and 3 tyrosine kinases. AZD4547 inhibited recombinant FGFR kinase activity in vitro and suppressed FGFR signaling and growth in tumor cell lines with deregulated FGFR expression. In a representative FGFR-driven human tumor xenograft model, oral administration of AZD4547 was well tolerated and resulted in potent dose-dependent antitumor activity, consistent with plasma exposure and pharmacodynamic modulation of tumor FGFR. Importantly, at efficacious doses, no evidence of anti-KDR-related effects were obsd., confirming the in vivo FGFR selectivity of AZD4547. Taken together, our findings show that AZD4547 is a novel selective small-mol. inhibitor of FGFR with potent antitumor activity against FGFR-deregulated tumors in preclin. models. AZD4547 is under clin. investigation for the treatment of FGFR-dependent tumors. Cancer Res; 72(8); 2045-56.
- 125Guagnano, V.; Furet, P.; Spanka, C.; Bordas, V.; Le Douget, M.; Stamm, C.; Brueggen, J.; Jensen, M. R.; Schnell, C.; Schmid, H.; Wartmann, M.; Berghausen, J.; Drueckes, P.; Zimmerlin, A.; Bussiere, D.; Murray, J.; Graus Porta, D. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase J. Med. Chem. 2011, 54, 7066– 7083 DOI: 10.1021/jm2006222[ACS Full Text], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1SrsrvK&md5=f9a2d742294cd3814e872bdd8add1ffaDiscovery of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), A Potent and Selective Inhibitor of the Fibroblast Growth Factor Receptor Family of Receptor Tyrosine KinaseGuagnano, Vito; Furet, Pascal; Spanka, Carsten; Bordas, Vincent; Le Douget, Mickael; Stamm, Christelle; Brueggen, Josef; Jensen, Michael R.; Schnell, Christian; Schmid, Herbert; Wartmann, Markus; Berghausen, Joerg; Drueckes, Peter; Zimmerlin, Alfred; Bussiere, Dirksen; Murray, Jeremy; Graus Porta, DianaJournal of Medicinal Chemistry (2011), 54 (20), 7066-7083CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the basis of its in vitro profile, compd. 1h (NVP-BGJ398) was selected for in vivo evaluation and showed significant antitumor activity in RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support the potential therapeutic use of 1h as a new anticancer agent.
- 126Angibaud, P. R.; Mevellec, L.; Saxty, G.; Adelinet, C.; Akkari, R.; Berdini, V.; Bonnet, P.; Bourgeois, M.; Bourdrez, X.; Cleasby, A.; Colombel, H.; Csoka, I.; Embrechts, W.; Freyne, E.; Gilissen, R.; Jovcheva, E.; King, P.; Lacrampe, J.; Lardeau, D.; Ligny, Y.; Mcclue, S.; Meerpoel, L.; Newell, D. R.; Page, M.; Papanikos, A.; Pasquier, E.; Pilatte, I.; Poncelet, V.; Querolle, O.; Rees, D. C.; Rich, S.; Roux, B.; Sement, E.; Simonnet, Y.; Squires, M.; Tronel, V.; Verhulst, T.; Vialard, J.; Willems, M.; Woodhead, S. J.; Wroblowski, B.; Murray, C. W.; Perera, T. Abstract 4748: Discovery of JNJ-42756493, a potent fibroblast growth factor receptor (FGFR) inhibitor using a fragment based approach Cancer Res. 2014, 74 (Suppl.) 4748 DOI: 10.1158/1538-7445.AM2014-4748
- 127Nakanishi, Y.; Akiyama, N.; Tsukaguchi, T.; Fujii, T.; Sakata, K.; Sase, H.; Isobe, T.; Morikami, K.; Shindoh, H.; Mio, T.; Ebiike, H.; Taka; Naoki, N.; Aoki, Y.; Ishii, N. The fibroblast growth factor receptor genetic status as a potential predictor for the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor Mol. Cancer Ther. 2014, 13, 2547– 2558 DOI: 10.1158/1535-7163.MCT-14-0248[Crossref], [PubMed], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVGju73F&md5=35629d891a421582022b0f6ae0496479The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR InhibitorNakanishi, Yoshito; Akiyama, Nukinori; Tsukaguchi, Toshiyuki; Fujii, Toshihiko; Sakata, Kiyoaki; Sase, Hitoshi; Isobe, Takehito; Morikami, Kenji; Shindoh, Hidetoshi; Mio, Toshiyuki; Ebiike, Hirosato; Taka, Naoki; Aoki, Yuko; Ishii, NobuyaMolecular Cancer Therapeutics (2014), 13 (11), 2547-2558CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-mol. inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family displayed clin. benefits in cohorts of patients with FGFR genetic alterations. However, to achieve more potent and prolonged activity in such populations, a selective FGFR inhibitor is still needed. Here, we report the identification of CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chem. scaffold. By interacting with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 displayed preferential antitumor activity against cancer cells with various FGFR genetic alterations in a panel of 327 cancer cell lines and in xenograft models. Because of its unique binding mode, CH5183284/Debio 1347 can inhibit FGFR2 harboring one type of the gatekeeper mutation that causes resistance to other FGFR inhibitors and block FGFR2 V564F-driven tumor growth. CH5183284/Debio 1347 is under clin. investigation for the treatment of patients harboring FGFR genetic alterations. Mol Cancer Ther; 13(11); 2547-58. ©2014 AACR.
- 128https://clinicaltrials.gov/ct2/show/NCT01975701 (accessed June 12, 2016) .
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- 130Elmlinger, M. W.; Deininger, M. H.; Schuett, B. S.; Meyermann, R.; Duffner, F.; Grote, E. H.; Ranke, M. B. In vivo expression of insulin-like growth factor-binding protein-2 in human gliomas increases with the tumor grade Endocrinology 2001, 142, 1652– 1658 DOI: 10.1210/endo.142.4.8084
- 131Chen, H. X.; Sharon, E. IGF-1R as an anti-cancer target—trials and tribulations Aizheng 2013, 32, 242– 252 DOI: 10.5732/cjc.012.10263[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVeltr3I&md5=5534aa8d4dbfefe5dd2e5248be888328IGF-1R as an anti-cancer target-trials and tribulationsChen, Helen X.; Sharon, EladChinese Journal of Cancer (2013), 32 (5), 242-252CODEN: CJCHDJ ISSN:. (Sun Yat-sen University Cancer Center)A review. Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clin. trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF-2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R-targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacol. features. Clin. activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small no. of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clin. trials involving patients with adult tumors, including non-small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clin. benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be crit. to success in future development.
- 132Mulvihill, M. J.; Cooke, A.; Rosenfeld-Franklin, M.; Buck, E.; Foreman, K.; Landfair, D.; O’Connor, M.; Pirritt, C.; Sun, Y.; Yao, Y.; Arnold, L. D.; Gibson, N. W.; Ji, Q. S. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-I receptor and insulin receptor Future Med. Chem. 2009, 1, 1153– 1171 DOI: 10.4155/fmc.09.89[Crossref], [PubMed], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVChs7zM&md5=c7583de9d57e3af55ff2fa0c3708fd93Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-I receptor and insulin receptorMulvihill, Mark J.; Cooke, Andrew; Rosenfeld-Franklin, Maryland; Buck, Elizabeth; Foreman, Ken; Landfair, Darla; O'Connor, Matthew; Pirritt, Caroline; Sun, Yingchaun; Yao, Yan; Arnold, Lee D.; Gibson, Neil W.; Ji, Qun-ShengFuture Medicinal Chemistry (2009), 1 (6), 1153-1171CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)The IGF-I receptor (IGF-IR) has been implicated in the promotion of tumorigenesis, metastasis and resistance to cancer therapies. Therefore, this receptor has become a major focus for the development of anticancer agents. Our lead optimization efforts that blended structure-based design and empirical medicinal chem. led to the discovery of OSI-906, a novel small-mol. dual IGF-IR/insulin receptor (IR) kinase inhibitor. OSI-906 potently and selectively inhibits autophosphorylation of both human IGF-IR and IR, displays in vitro antiproliferative effects in a variety of tumor cell lines and shows robust in vivo anti-tumor efficacy in an IGF-IR-driven xenograft model when administered orally once daily. OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-IR/IR kinase inhibitor with favorable preclin. drug-like properties, which has demonstrated in vivo efficacy in tumor models and is currently in clin. testing.
- 133Carboni, J. M.; Wittman, M.; Yang, Z.; Lee, F.; Greer, A.; Hurlburt, W.; Hillerman, S.; Cao, C.; Cantor, G. H.; Dell-John, J.; Chen, C.; Discenza, L.; Menard, K.; Li, A.; Trainor, G.; Vyas, D.; Kramer, R.; Attar, R. M.; Gottardis, M. M. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR Mol. Cancer Ther. 2009, 8, 3341– 3349 DOI: 10.1158/1535-7163.MCT-09-0499[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFCitb3F&md5=1f348da6d076373aaf9296ebfcfc5542BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IRCarboni, Joan M.; Wittman, Mark; Yang, Zheng; Lee, Francis; Greer, Ann; Hurlburt, Warren; Hillerman, Stephen; Cao, Carolyn; Cantor, Glenn H.; Dell-John, Janet; Chen, Cliff; Discenza, Lorell; Menard, Krista; Li, Aixin; Trainor, George; Vyas, Dolatrai; Kramer, Robert; Attar, Ricardo M.; Gottardis, Marco M.Molecular Cancer Therapeutics (2009), 8 (12), 3341-3349CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compd. caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a min. ED of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clin. outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.
- 134Vasilcanu, D.; Girnita, A.; Girnita, L.; Vasilcanu, R.; Axelson, A.; Larsson, O. The cyclolignan PPP induces activation loop-specific inhibition of tyrosine phosphorylation of the insulin-like growth factor-1 receptor. Link to the phosphatidyl inositol-3 kinase/Akt apoptotic pathway Oncogene 2004, 23, 7854– 7862 DOI: 10.1038/sj.onc.1208065
- 135Guz, N. R.; Leuser, H.; Goldman, E. Process development and multikilogram syntheses of XL228 utilizing a regioselective isoxazole formation and a selective SNAr reaction to a pyrimidine core Org. Process Res. Dev. 2013, 17, 1066– 1073 DOI: 10.1021/op400137m
- 136Rodon, J.; De Santos, V.; Ferry, R. J.; Kurzrock, R. Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials Mol. Cancer Ther. 2008, 7, 2575– 2588 DOI: 10.1158/1535-7163.MCT-08-0265[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFSms7jJ&md5=d37e37d3752231ef2c152110c1e85a66Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: Lessons from the first clinical trialsRodon, Jordi; De Santos, Victoria; Ferry, Robert Jean, Jr.; Kurzrock, RazelleMolecular Cancer Therapeutics (2008), 7 (9), 2575-2588CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)A review. The insulin-like growth factor-I receptor (IGF-IR) was first cloned in 1986. Since then, intense work has defined classic phosphorelays activated via the IGF-IR, which regulate cell proliferation, apoptosis, motility, and fate. The understanding of the roles of hormones in cancer and the growth hormone-IGF-IGF-binding protein axis specifically has yield to a second wave of development: the design of specific inhibitors that interrupt the signaling assocd. with this axis. The ability to manipulate these pathways holds not only significant therapeutic implications but also increase the chance of deeper insight about the role of the axis in carcinogenesis and metastasis. Nowadays, >25 mols. with the same goal are at different stages of development. Here, we review the clin. and preclin. experience with the two most-investigated strategies, tyrosine kinase inhibitors and monoclonal antibodies, and the advantages and disadvantages of each strategy, as well as other alternatives and possible drug combinations. We also review the biomarkers explored in the first clin. trials, the strategies that have been explored thus far, and the clin. trials that are going to explore their role in cancer treatment.
- 137Halvorson, K. G.; Barton, K. L.; Schroeder, K.; Misuraca, K. L.; Hoeman, C.; Chung, A.; Crabtree, D. M.; Cordero, F. J.; Singh, R.; Spasojevic, I.; Berlow, N.; Pal, R.; Becher, O. J. A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent PLoS One 2015, 10, e0118926 DOI: 10.1371/journal.pone.0118926
- 138Boston-Howes, W.; Williams, E. O.; Bogush, A.; Scolere, M.; Pasinelli, P.; Trotti, D. Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: therapeutic implications for amyotrophic lateral sclerosis Exp. Neurol. 2008, 213, 229– 237 DOI: 10.1016/j.expneurol.2008.06.010[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVSgurbK&md5=234cf9e059cef90a66c4cea69a656195Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: Therapeutic implications for amyotrophic lateral sclerosisBoston-Howes, William; Williams, Eric O.; Bogush, Alexey; Scolere, Maura; Pasinelli, Piera; Trotti, DavideExperimental Neurology (2008), 213 (1), 229-237CODEN: EXNEAC; ISSN:0014-4886. (Elsevier Inc.)Synaptic accumulation of glutamate causes neuronal death in many neurodegenerative pathologies including amyotrophic lateral sclerosis. Drugs capable of increasing glutamate uptake could therefore be therapeutically effective. We screened in a cell-based assay a library of 1040 FDA-approved drugs and nutrients for compds. that could enhance glutamate uptake. Nordihydroguaiaretic acid (NDGA), an anti-inflammatory drug that inhibits lipoxygensases, potently enhanced glutamate uptake in MN-1 cells. Given s.c. at 1 mg/day for 30 days in mice, NDGA increased glutamate uptake in spinal cord synaptosomes persistently throughout the treatment. However, when administered following the same regimen to the SOD1-G93A transgenic mouse model of ALS at disease onset, NDGA did not extend survival of these mice. We found that NDGA failed to sustain increased glutamate uptake in the SOD1-G93A mice despite an initial upregulation measured during the first 10 days of treatment. SOD1-G93A mice displayed a progressive increase in spinal cord expression levels of the efflux transporter P-glycoprotein beginning at disease onset. This increase was not mediated by the NDGA treatment because it was measured in untreated SOD1-G93A mice. Since P-glycoproteins control the extrusion of a broad range of toxins and xenobiotics and are responsible for drug resistance in many diseases including cancer and brain diseases such as epilepsy, we propose that the failure of NDGA in maintaining glutamate uptake upregulated in SOD1-G93A mice and its therapeutic inefficacy are due to acquired pharmacoresistance mediated by the increased expression of P-glycoprotein.
- 139Parsons, D. W.; Jones, S.; Zhang, X.; Lin, J. C.-H.; Leary, R. J.; Angenendt, P.; Mankoo, P.; Carter, H.; Siu, I.-M.; Gallia, G. L.; Olivi, A.; McLendon, R.; Rasheed, B. A.; Keir, S.; Nikolskaya, T.; Nikolsky, Y.; Busam, D. A.; Tekleab, H.; Diaz, L. A.; Hartigan, J.; Smith, D. R.; Strausberg, R. L.; Marie, S. K. N.; Shinjo, S. M. O.; Yan, H.; Riggins, G. J.; Bigner, D. D.; Karchin, R.; Papadopoulos, N.; Parmiqiani, G.; Vogelstein, B.; Velculescu, V. E.; Kinzler, K. W. An integrated genomic analysis of human glioblastoma multiforme Science 2008, 321, 1807– 1812 DOI: 10.1126/science.1164382[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFCrtLrE&md5=88c9e87c4b9dc8ebedcaa2b5d9f3ce13An Integrated genomic analysis of human glioblastoma multiformeParsons, D. Williams; Jones, Sian; Zhang, Xiaosong; Lin, Jimmy Cheng-Ho; Leary, Rebecca J.; Angenendt, Philipp; Mankoo, Parminder; Carter, Hannah; Siu, I.-Mei; Gallia, Gary L.; Olivi, Alessandro; McLendon, Roger; Rasheed, B. Ahmed; Keir, Stephen; Nikolskaya, Tatiana; Nikolsky, Yuri; Busam, Dana A.; Tekleab, Hanna; Diaz, Luis A., Jr.; Hartigan, James; Smith, Doug R.; Strausberg, Robert L.; Marie, Suely Kazue Nagahashi; Shinjo, Sueli Mieko Oba; Yan, Hai; Riggins, Gregory J.; Bigner, Darell D.; Karchin, Rachel; Papadopoulos, Nick; Parmigiani, Giovanni; Vogelstein, Bert; Velculescu, Victor E.; Kinzler, Kenneth W.Science (Washington, DC, United States) (2008), 321 (5897), 1807-1812CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A review based on author's research. Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, detd. the presence of amplifications and deletions using high-d. oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive anal. led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were assocd. with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.
- 140(a) Paugh, B. S.; Broniscer, A.; Qu, C.; Miller, C. P.; Zhang, J.; Tatevossian, R. G.; Olson, J. M.; Geyer, J. R.; Chi, S. N.; da Silva, N. S.; Onar-Thomas, A.; Baker, J. N.; Gajjar, A.; Ellison, D. W.; Baker, Z. J. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma J. Clin. Oncol. 2011, 29, 3999– 4006 DOI: 10.1200/JCO.2011.35.5677[Crossref], [PubMed], [CAS], Google Scholar140ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFams7bP&md5=f7c34fb55df46d685514103b4c66fb06Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine gliomaPaugh, Barbara S.; Broniscer, Alberto; Qu, Chunxu; Miller, Claudia P.; Zhang, Junyuan; Tatevossian, Ruth G.; Olson, James M.; Geyer, J. Russell; Chi, Susan N.; Saba da Silva, Nasjla; Onar-Thomas, Arzu; Baker, Justin N.; Gajjar, Amar; Ellison, David W.; Baker, Suzanne J.Journal of Clinical Oncology (2011), 29 (30), 3999-4006CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy no. abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas. Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21 % had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar. DIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.(b) Warren, K. E.; Killian, K.; Suuriniemi, M.; Wang, Y.; Quezado, M.; Meltzer, P. S. Genomic aberrations in pediatric diffuse intrinsic pontine gliomas Neuro-Oncology 2012, 14, 326– 332 DOI: 10.1093/neuonc/nor190
- 141Toogood, P. L.; Harvey, P. J.; Repine, J. T.; Sheehan, D. J.; VanderWel, S. N.; Zhou, H.; Keller, P. R.; McNamara, D. J.; Sherry, D.; Zhu, T.; Brodfuehrer, J.; Choi, C.; Barvian, M. R.; Fry, D. W. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6 J. Med. Chem. 2005, 48, 2388– 2406 DOI: 10.1021/jm049354h[ACS Full Text], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXitVGisL0%253D&md5=23cbe58426ff1975695712db7c1b128aDiscovery of a Potent and Selective Inhibitor of Cyclin-Dependent Kinase 4/6Toogood, Peter L.; Harvey, Patricia J.; Repine, Joseph T.; Sheehan, Derek J.; VanderWel, Scott N.; Zhou, Hairong; Keller, Paul R.; McNamara, Dennis J.; Sherry, Debra; Zhu, Tong; Brodfuehrer, Joanne; Choi, Chung; Barvian, Mark R.; Fry, David W.Journal of Medicinal Chemistry (2005), 48 (7), 2388-2406CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A pharmacol. approach to inhibition of cyclin-dependent kinases 4 and 6 (Cdk4/6) using highly selective small mol. inhibitors has the potential to provide novel cancer therapies for clin. use. Achieving high levels of selectivity for Cdk4/6, vs. other ATP-dependent kinases, presents a significant challenge. The pyrido[2,3-d]pyrimidin-7-one template provides an effective platform for the inhibition of a broad cross-section of kinases, including Cdks. It is now demonstrated that the modification of pyrido[2,3-d]pyrimidin-7-ones to include a 2-aminopyridine side chain at the C2-position provides inhibitors with exquisite selectivity for Cdk4/6 in vitro. This selectivity profile is recapitulated in cells where the most selective inhibitors create a G1 block at concns. up to 100-fold the IC50 for cell proliferation. On the basis of its selectivity profile and pharmacokinetic profile, compd. I (PD 0332991) was identified as a drug candidate for the treatment of cancer.
- 142Barton, K. L.; Misuraca, K.; Cordero, F.; Dobrikova, E.; Min, H. D.; Gromeier, M.; Kirsch, D. G.; Becher, O. J. PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma PLoS One 2013, 8, e77639 DOI: 10.1371/journal.pone.0077639
- 143Michaud, K.; Solomon, D. A.; Oermann, E.; Kim, J.-S.; Zhong, W.-Z.; Prados, M. D.; Ozawa, T.; James, C. D.; Waldman, T. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts Cancer Res. 2010, 70, 3228– 3238 DOI: 10.1158/0008-5472.CAN-09-4559
- 144Parrish, K. E.; Pokorny, J. L.; Mittapalli, R. K.; Bakken, K.; Sarkaria, J. N.; Elmquist, W. F. Efflux transporters at the blood-brain barrier limit delivery and efficacy of CDK4/6 inhibitor palbociclib (PD-0332991) in an orthotopic brain tumor model J. Pharmacol. Exp. Ther. 2015, 355, 264– 271 DOI: 10.1124/jpet.115.228213[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhslekuro%253D&md5=d40558cdcd30db24808eb55393607cbcEfflux transporters at the blood-brain barrier limit delivery and efficacy of cyclin-dependent kinase 4/6 inhibitor palbociclib (PD-0332991) in an orthotopic brain tumor modelParrish, Karen E.; Pokorny, Jenny; Mittapalli, Rajendar K.; Bakken, Katrina; Sarkaria, Jann N.; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2015), 355 (2), 264-271CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)6-Acetyl-8-cyclopentyl-5-methyl-2-([5-(piperazin-1-yl)pyridin-2- yl]amino)pyrido(2,3-d)pyrimidin-7(8H)-one [palbociclib (PD- 0332991)] is a cyclin-dependent kinase 4/6 inhibitor approved for the treatment of metastatic breast cancer and is currently undergoing clin. trials for many solid tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and has limited treatment options. The cyclin-dependent kinase 4/6 pathway is commonly dysregulated in GBM and is a promising target in treating this devastating disease. The blood-brain barrier (BBB) limits the delivery of drugs to invasive regions of GBM, where the efflux transporters P-glycoprotein and breast cancer resistance protein can prevent treatments from reaching the tumor. The purpose of this study was to examine the mechanisms limiting the effectiveness of palbociclib therapy in an orthotopic xenograft model. The in vitro intracellular accumulation results demonstrated that palbociclib is a substrate for both P-glycoprotein and breast cancer resistance protein. In vivo studies in transgenic mice confirmed that efflux transport is responsible for the limited brain distribution of palbociclib. There was an ∼115-fold increase in brain exposure at steady state in the transporter deficient mice when compared with wild-type mice, and the efflux inhibitor elacridar significantly increased palbociclib brain distribution. Efficacy studies demonstrated that palbociclib is an effective therapy when GBM22 tumor cells are implanted in the flank, but ineffective in an orthotopic (intracranial) model. Moreover, doses designed to mimic brain exposure were ineffective in treating flank tumors. These results demonstrate that efflux transport in the BBB is involved in limiting the brain distribution of palbociclib and this has crit. implications in detg. effective dosing regimens of palbociclib therapy in the treatment of brain tumors.
- 145Gelbert, L. M.; Cai, S.; Lin, X.; Sanchez-Martinez, C.; del Prado, M.; Lallena, M. J.; Torres, R.; Ajamie, R. T.; Wishart, G. N.; Flack, R. S.; Neubauer, B. L.; Young, J.; Chan, E. M.; Iversen, P.; Cronier, D.; Kreklau, E.; de Dios, A. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine Invest. New Drugs 2014, 32, 825– 837 DOI: 10.1007/s10637-014-0120-7[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVWrt7%252FN&md5=a90fee83bfe8da7e4a7474ccf02fc59aPreclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabineGelbert, Lawrence M.; Cai, Shufen; Lin, Xi; Sanchez-Martinez, Concepcion; del Prado, Miriam; Lallena, Maria Jose; Torres, Raquel; Ajamie, Rose T.; Wishart, Graham N.; Flack, Robert Steven; Neubauer, Blake Lee; Young, Jamie; Chan, Edward M.; Iversen, Philip; Cronier, Damien; Kreklau, Emiko; de Dios, AlfonsoInvestigational New Drugs (2014), 32 (5), 825-837CODEN: INNDDK; ISSN:0167-6997. (Springer)The G1 restriction point is crit. for regulating the cell cycle and is controlled by the Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This pathway is important because of its inactivation in a majority of human tumors. Transition through the restriction point requires phosphorylation of retinoblastoma protein (Rb) by CDK4/6, which are highly validated cancer drug targets. We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 h after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different histologies in tumor-bearing mice. LY2835219 is effective and well tolerated when administered up to 56 days in immunodeficient mice without significant loss of body wt. or tumor outgrowth. In calu-6 xenografts, LY2835219 in combination with gemcitabine enhanced in vivo antitumor activity without a G1 cell cycle arrest, but was assocd. with a redn. of ribonucleotide reductase expression. These results suggest LY2835219 may be used alone or in combination with std.-of-care cytotoxic therapy. In summary, we have identified a potent, orally active small-mol. inhibitor of CDK4/6 that is active in xenograft tumors. LY2835219 is currently in clin. development.
- 146Raub, T. J.; Wishart, G. N.; Kulanthaivel, P.; Staton, B. A.; Ajamie, R. T.; Sawada, G. A.; Gelbert, L. M.; Shannon, H. E.; Sanchez-Martinez, C.; De Dios, A. Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft Drug Metab. Dispos. 2015, 43, 1360– 1371 DOI: 10.1124/dmd.114.062745[Crossref], [PubMed], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlGrtbrL&md5=711886dd28d0e9ef3367183c8191ae1cBrain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograftRaub, Thomas J.; Wishart, Graham N.; Kulanthaivel, Palaniappan; Staton, Brian A.; Ajamie, Rose T.; Sawada, Geri A.; Gelbert, Lawrence M.; Shannon, Harlan E.; Sanchez-Martinez, Concepcion; De Dios, AlfonsoDrug Metabolism & Disposition (2015), 43 (9), 1360-1371CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. Targeting the CDK4/CDK6-cyclin D1-Rb-p16/ink4a pathway using a potent CDK4 and CDK6 kinase inhibitor has potential for treating primary central nervous system tumors such as glioblastoma and some peripheral tumors with high incidence of brain metastases. We compared central nervous system exposures of two orally bioavailable CDK4 and CDK6 inhibitors: abemaciclib, which is currently in advanced clin. development, and palbociclib (IBRANCE; Pfizer), which was recently approved by the U.S. Food and Drug Administration. Abemaciclib antitumor activity was assessed in s.c. and orthotopic glioma models alone and in combination with std. of care temozolomide (TMZ). Both inhibitors were substrates for xenobiotic efflux transporters P-glycoprotein and breast cancer resistant protein expressed at the blood-brain barrier. Brain Kp,uu values were less than 0.2 after an equimolar i.v. dose indicative of active efflux but were approx. 10-fold greater for abemaciclib than palbociclib. Kp,uu increased 2.8- and 21-fold, resp., when similarly dosed in P-gp-deficient mice. Abemaciclib had brain area under the curve (0-24 h) Kp,uu values of 0.03 in mice and 0.11 in rats after a 30 mg/kg p.o. dose. Orally dosed abemaciclib significantly increased survival in a rat orthotopic U87MG xenograft model compared with vehicle-treated animals, and efficacy coincided with a dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and CDK6 Ki values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats similar to TMZ, and the combination of abemaciclib and TMZ was additive or greater than additive. These data show that abemaciclib crosses the blood-brain barrier and confirm that both CDK4 and CDK6 inhibitors reach unbound brain levels in rodents that are expected to produce enzyme inhibition; however, abemaciclib brain levels are reached more efficiently at presumably lower doses than palbociclib and are potentially on target for a longer period of time.
- 147Sanchez-Martinez, C.; Gelbert, L. M.; Shannon, H.; De Dios, A.; Staton, B. A.; Ajamie, R. T.; Sawada, G.; Wishart, G. N.; Raub, T. J. Abstract B234: LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts Mol. Cancer Ther. 2011, 10, B234 DOI: 10.1158/1535-7163.TARG-11-B234
- 148https://clinicaltrials.gov/ct2/show/NCT02308020 (accessed June 12, 2016) .
- 149Asghar, U.; Witkiewicz, A. K.; Turner, N. C.; Knudsen, E. S. The history and future of targeting cyclin-dependent kinases in cancer therapy Nat. Rev. Drug Discovery 2015, 14, 130– 146 DOI: 10.1038/nrd4504[Crossref], [PubMed], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjvVCrtLc%253D&md5=113bcd2e99a8267119d180670d3c7761The history and future of targeting cyclin-dependent kinases in cancer therapyAsghar, Uzma; Witkiewicz, Agnieszka K.; Turner, Nicholas C.; Knudsen, Erik S.Nature Reviews Drug Discovery (2015), 14 (2), 130-146CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Cancer represents a pathol. manifestation of uncontrolled cell division; therefore, it has long been anticipated that our understanding of the basic principles of cell cycle control would result in effective cancer therapies. In particular, cyclin-dependent kinases (CDKs) that promote transition through the cell cycle were expected to be key therapeutic targets because many tumorigenic events ultimately drive proliferation by impinging on CDK4 or CDK6 complexes in the G1 phase of the cell cycle. Moreover, perturbations in chromosomal stability and aspects of S phase and G2/M control mediated by CDK2 and CDK1 are pivotal tumorigenic events. Translating this knowledge into successful clin. development of CDK inhibitors has historically been challenging, and numerous CDK inhibitors have demonstrated disappointing results in clin. trials. Here, we review the biol. of CDKs, the rationale for therapeutically targeting discrete kinase complexes and historical clin. results of CDK inhibitors. We also discuss how CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clin. activity.
- 150Cheng, C. K.; Gustafson, W. C.; Charron, E.; Houseman, B. T.; Zunder, E.; Goga, A.; Gray, N. S.; Pollok, B.; Oakes, S. A.; James, C. D.; Shokat, K. M.; Weiss, W. A.; Fan, Q. W. Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 12722– 12727 DOI: 10.1073/pnas.1202492109
- 151Senderowicz, A. M. Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials Invest. New Drugs 1999, 17, 313– 320 DOI: 10.1023/A:1006353008903
- 152Newcomb, E. W.; Tamasdan, C.; Entzminger, Y.; Arena, E.; Schnee, T.; Kim, M.; Crisan, D.; Lukyanov, Y.; Miller, D. C.; Zagzag, D. Flavopiridol inhibits the growth of GL261 gliomas in vivo Cell Cycle 2004, 3, 218– 222 DOI: 10.4161/cc.3.2.667
- 153Zhou, L.; Schmidt, K.; Nelson, F. R.; Zelesky, V.; Troutman, M. D.; Feng, B. The effect of breast cancer resistance protein and P-glycoprotein on the brain penetration of flavopiridol, imatinib mesylate (Gleevec), prazosin, and 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic acid (PF-407288) in mice Drug Metab. Dispos. 2009, 37, 946– 955 DOI: 10.1124/dmd.108.024489[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlsVWitLo%253D&md5=422881b70fa04474e0242a9c3a095093The effect of breast cancer resistance protein and P-glycoprotein on the brain penetration of flavopiridol, imatinib mesylate (Gleevec), prazosin, and 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic acid (PF-407288) in miceZhou, Lin; Schmidt, Kari; Nelson, Frederick R.; Zelesky, Veronica; Troutman, Matthew D.; Feng, BoDrug Metabolism and Disposition (2009), 37 (5), 946-955CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)The role of breast cancer resistance protein (Bcrp) and the combined activities of Bcrp and P-glycoprotein (P-gp, Mdr1a/1b) in limiting the brain penetration of drugs at the blood-brain barrier (BBB) were investigated using wild-type FVB, Mdr1a/1b(-/-), (-/-), Bcrp(-/-), and Mdr1a/1b(-/-), (-/-)Bcrp(-/-) mice. Four drugs, flavopiridol, imatinib mesylate (Gleevec), PF-407288, and prazosin, with different transport specificity for BCRP/Bcrp and MDR1/Mdr1a were selected, and the drug levels in plasma, cerebrospinal fluid, and brain of mice were detd. Flavopiridol and prazosin were identified as substrates for both mouse Bcrp and Mdr1a with greater transport assocd. with Bcrp. The brain/plasma (B/P) ratios at 0.5 and 2 h in Mdr1a/1b(-/-), (-/-) and Bcrp(-/-) mice were 1- to 2-fold for both compds., whereas the ratios in Mdr1a/1b(-/-), (-/-)Bcrp(-/-) mice were more than 5-fold of those obsd. in FVB mice. For imatinib, a better substrate of P-gp than Bcrp, the B/P ratios in Bcrp(-/-) were comparable to those in FVB mice, whereas the B/P ratios in Mdr1a/1b(-/-), (-/-) and Mdr1a/1b(-/-), (-/-)Bcrp(-/-) mice were more than 4- and 28-fold of those in FVB mice at both time points, resp. Finally, the Bcrp-specific substrate PF-407288 exhibited comparable B/P ratios in Mdr1a/1b(-/-), (-/-) and Bcrp(-/-) mice and slightly but significantly increased B/P ratios in Mdr1a/1b(-/-), (-/-)Bcrp(-/-) mice compared with those in FVB mice. The B/P ratios of compds. in Mdr1a/1b(-/-), (-/-)Bcrp(-/-) mice compared with those in Mdr1a/1b(-/-), (-/-) mice clearly demonstrate that Bcrp impairs the brain penetration of its substrates. Moreover, P-gp and Bcrp at BBB function synergistically to limit the brain penetration of shared substrates.
- 154Vita, M.; Abdel-Rehim, M.; Olofsson, S.; Hassan, Z.; Meurling, L.; Siden, A.; Siden, M.; Pettersson, T.; Hassan, M. Tissue distribution, pharmacokinetics and identification of roscovitine metabolites in rat Eur. J. Pharm. Sci. 2005, 25, 91– 103 DOI: 10.1016/j.ejps.2005.02.001[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjs1Kmsro%253D&md5=c4b7c6c0f7876cb67fb7ee6c91326262Tissue distribution, pharmacokinetics and identification of roscovitine metabolites in ratVita, Marina; Abdel-Rehim, Mohamed; Olofsson, Susanne; Hassan, Zuzana; Meurling, Lennart; Siden, Aake; Siden, Mabel; Pettersson, Tommy; Hassan, MoustaphaEuropean Journal of Pharmaceutical Sciences (2005), 25 (1), 91-103CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)The pharmacokinetics, biodistribution and the metabolic pathway of roscovitine were investigated in Sprague-Dawley rats after a single i.v. dose of 25 mg/kg. Blood, lungs, kidney, liver, testis, adipose tissue, spleen and brain were removed at different time-points. Plasma and tissue samples were analyzed using high performance liq. chromatog. The metabolites were identified using liq. chromatog./tandem mass spectrometry and NMR spectroscopy. Roscovitine (MW = 354) was cleared rapidly from circulation and highly distributed to the tissues. The elimination half-life of roscovitine in plasma and tissues was short (<30 min). A major metabolite (M1) was obsd. mainly in plasma and in lower levels in all other tissues. M1 was identified as conversion of the hydroxyl-group at C2 to carboxylic acid (MW = 368). A second metabolite (M2) was obsd. mainly in liver and kidney and identified as a hydroxylation product of the C8 of the purine-ring (MW = 370). A third metabolite (M3) was found in several organs and corresponded to N-dealkylation of the N9-iso-Pr side-chain (MW = 312). Roscovitine concns. in the brain were 30% of that obsd. in plasma, however no metabolites were detected in brain. In this investigation, three major metabolites of roscovitine were isolated and identified. Also, it was shown that roscovitine eliminates rapidly from both blood and tissues.
- 155Rajnai, Z.; Mehn, D.; Beery, E.; Okyar, A.; Jani, M.; Toth, G. K.; Fulop, F.; Levi, F.; Krajcsi, P. ATP-binding cassette B1 transports seliciclib (R-roscovitine), a cyclin-dependent kinase inhibitor Drug Metab. Dispos. 2010, 38, 2000– 2006 DOI: 10.1124/dmd.110.032805
- 156Paruch, K.; Dwyer, M. P.; Alvarez, C.; Brown, C.; Chan, T. Y.; Doll, R. J.; Keertikar, K.; Knutson, C.; McKittrick, B.; Rivera, J.; Rossman, R.; Tucker, G.; Fischmann, T.; Hruza, A.; Madison, V.; Nomeir, A. A.; Wang, Y.; Kirschmeier, P.; Lees, E.; Parry, D.; Sqambellone, N.; Seghezzi, W.; Schultz, L.; Shanahan, F.; Wiswell, D.; Xu, X.; Zhou, Q.; James, R. A.; Paradkar, V. M.; Park, H.; Rokosz, L. R.; Stauffer, T. M.; Guzi, T. J. Discovery of dinaciclib (SCH 727965): a potent and selective inhibitor of cyclin-dependent kinases ACS Med. Chem. Lett. 2010, 1, 204– 208 DOI: 10.1021/ml100051d[ACS Full Text], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmtFWis78%253D&md5=3b982547e064f658748fe4887a208659Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent KinasesParuch, Kamil; Dwyer, Michael P.; Alvarez, Carmen; Brown, Courtney; Chan, Tin-Yau; Doll, Ronald J.; Keertikar, Kerry; Knutson, Chad; McKittrick, Brian; Rivera, Jocelyn; Rossman, Randall; Tucker, Greg; Fischmann, Thierry; Hruza, Alan; Madison, Vincent; Nomeir, Amin A.; Wang, Yaolin; Kirschmeier, Paul; Lees, Emma; Parry, David; Sgambellone, Nicole; Seghezzi, Wolfgang; Schultz, Lesley; Shanahan, Frances; Wiswell, Derek; Xu, Xiaoying; Zhou, Quiao; James, Ray A.; Paradkar, Vidyadhar M.; Park, Haengsoon; Rokosz, Laura R.; Stauffer, Tara M.; Guzi, Timothy J.ACS Medicinal Chemistry Letters (2010), 1 (5), 204-208CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncol. therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clin. evaluation.
- 157Jane, E. P.; Premkumar, D. R.; Cavaleri, J. M.; Sutera, P. A.; Rajasekar, T.; Pollack, I. F. Dinaciclib, a cyclin-dependent kinase inhibitor promotes proteasomal degradation of Mcl-1 and enhances glioma cell lines J. Pharmacol. Exp. Ther. 2016, 356, 354– 365 DOI: 10.1124/jpet.115.230052[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpvVelsrc%253D&md5=0f25eb87db524546cb86ca6093150792Dinaciclib, a cyclin-dependent kinase inhibitor promotes proteasomal degradation of Mcl-1 and enhances ABT-737-mediated cell death in malignant human glioma cell linesJane, Esther P.; Premkumar, Daniel R.; Cavaleri, Jonathon M.; Sutera, Philip A.; Rajasekar, Thatchana; Pollack, Ian F.Journal of Pharmacology and Experimental Therapeutics (2016), 356 (2), 354-365CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)The prognosis for malignant glioma, the most common brain tumor, is still poor, underscoring the need to develop novel treatment strategies. Because glioma cells commonly exhibit genomic alterations involving genes that regulate cell-cycle control, there is a strong rationale for examg. the potential efficacy of strategies to counteract this process. In this study, we examd. the antiproliferative effects of the cyclin-dependent kinase inhibitor dinaciclib in malignant human glioma cell lines, with intact, deleted, or mutated p53 or phosphatase and tensin homolog on chromosome 10; intact or deleted or p14ARF or wild-type or amplified epidermal growth factor receptor. Dinaciclib inhibited cell proliferation and induced cell-cycle arrest at the G2/M checkpoint, independent of p53 mutational status. In a std. 72-h 3-[4,5-dimethylthiazol-2yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H, tetrazolium (MTS) assay, at clin. relevant concns., dose-dependent antiproliferative effects were obsd., but cell death was not induced. Moreover, the combination of conventional chemotherapeutic agents and various growth-signaling inhibitors with dinaciclib did not yield synergistic cytotoxicity. In contrast, combination of the Bcl-2/Bcl-xL inhibitors ABT-263 (4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide) or ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) with dinaciclib potentiated the apoptotic response induced by each single drug. The synergistic killing by ABT-737 with dinaciclib led to cell death accompanied by the hallmarks of apoptosis, including an early loss of the mitochondrial transmembrane potential; the release of cytochrome c, smac/DIABLO, and apoptosis-inducing factor; phosphatidylserine exposure on the plasma membrane surface and activation of caspases and poly ADP-ribose polymerase. Mechanistic studies revealed that dinaciclib promoted proteasomal degrdn. of Mcl-1. These observations may have important clin. implications for the design of exptl. treatment protocols for malignant human glioma.
- 158Loschmann, N.; Michaelis, M.; Rothweiler, F.; Zehner, R.; Cinati, J.; Voges, Y.; Sharifi, M.; Riecken, K.; Meyer, J.; von Deimling, A.; Fichter, I.; Ghafourian, T.; Westermann, F.; Cinatl, J. Testing of SNS-032 in a panel of human neuroblastoma cell lines with acquired resistance to a broad range of drugs Transl. Oncol. 2013, 6, 685– 696 DOI: 10.1593/tlo.13544[Crossref], [PubMed], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2czpt12ruw%253D%253D&md5=4ac4520700c6a093dfebba0b09cda08fTesting of SNS-032 in a Panel of Human Neuroblastoma Cell Lines with Acquired Resistance to a Broad Range of DrugsLoschmann Nadine; Rothweiler Florian; Cinatl Jaroslav; Voges Yvonne; Cinatl Jindrich Jr; Michaelis Martin; Zehner Richard; Sharifi Mohsen; Ghafourian Taravat; Riecken Kristoffer; Meyer Jochen; von Deimling Andreas; Fichtner Iduna; Westermann FrankTranslational oncology (2013), 6 (6), 685-96 ISSN:.Novel treatment options are needed for the successful therapy of patients with high-risk neuroblastoma. Here, we investigated the cyclin-dependent kinase (CDK) inhibitor SNS-032 in a panel of 109 neuroblastoma cell lines consisting of 19 parental cell lines and 90 sublines with acquired resistance to 14 different anticancer drugs. Seventy-three percent of the investigated neuroblastoma cell lines and all four investigated primary tumor samples displayed concentrations that reduce cell viability by 50% in the range of the therapeutic plasma levels reported for SNS-032 (<754 nM). Sixty-two percent of the cell lines and two of the primary samples displayed concentrations that reduce cell viability by 90% in this concentration range. SNS-032 also impaired the growth of the multidrug-resistant cisplatin-adapted UKF-NB-3 subline UKF-NB-3(r)CDDP(1000) in mice. ABCB1 expression (but not ABCG2 expression) conferred resistance to SNS-032. The antineuroblastoma effects of SNS-032 did not depend on functional p53. The antineuroblastoma mechanism of SNS-032 included CDK7 and CDK9 inhibition-mediated suppression of RNA synthesis and subsequent depletion of antiapoptotic proteins with a fast turnover rate including X-linked inhibitor of apoptosis (XIAP), myeloid cell leukemia sequence 1 (Mcl-1), baculoviral IAP repeat containing 2 (BIRC2; cIAP-1), and survivin. In conclusion, CDK7 and CDK9 represent promising drug targets and SNS-032 represents a potential treatment option for neuroblastoma including therapy-refractory cases.
- 159Kamath, A. V.; Chong, S.; Chang, M.; Marthe, P. H. P-glycoprotein plays a role in the oral absorption of BMS-387032, a potent cyclin-dependent kinase 2 inhibitor, in rats Cancer Chemother. Pharmacol. 2005, 55, 110– 116 DOI: 10.1007/s00280-004-0873-3[Crossref], [PubMed], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVGgtLzP&md5=728f59f80ef17fee59b85837e9d66885P-glycoprotein plays a role in the oral absorption of BMS-387032, a potent cyclin-dependent kinase 2 inhibitor, in ratsKamath, Amrita V.; Chong, Saeho; Chang, Ming; Marathe, Punit H.Cancer Chemotherapy and Pharmacology (2005), 55 (2), 110-116CODEN: CCPHDZ; ISSN:0344-5704. (Springer GmbH)Purpose: BMS-387032, a novel cyclin-dependent kinase 2 inhibitor, is currently in phase I clin. trials for anticancer therapy. The oral bioavailability of BMS-387032 has been found to be about 31 in rats. Absorption and first-pass metab. were evaluated as possible reasons for the incomplete oral bioavailability in rats. Methods: Male Sprague-Dawley rats were given single doses of BMS-387032 intraarterially (9.1 mg/kg), orally (9.1 mg/kg), or intraportally (10 mg/kg). The routes of excretion of BMS-387032 after i.v. dosing were investigated in bile-duct-cannulated rats. The rate of metab. of BMS-387032 was investigated in liver microsomes. The permeability of BMS-387032 was evaluated using Caco-2 cells, an in vitro model of the intestinal epithelium. To det. if BMS-387032 was a P-glycoprotein substrate, brain uptake studies were conducted in P-glycoprotein knockout vs. wildtype mice. Results: The exposure in rats after an intraportal dose was similar to that after an intraarterial dose, indicating that absorption may play a greater role than liver first-pass metab. in the low oral bioavailability seen in rats. After an i.v. dose, the percent of dose excreted unchanged in the urine and bile over a 9-h period was 28 and 11, resp. In vitro studies in rat liver microsomes showed low rates of metab. of BMS-387032. The Caco-2 cell permeability of BMS-387032 was <15 nm/s in the apical to basolateral direction, and 161 nm/s in the basolateral to apical direction, indicating that it may be a substrate for an intestinal efflux transporter. A P-glycoprotein binding assay showed that BMS-387032 might be a P-glycoprotein modulator. Brain penetration studies in mice showed brain levels of BMS-387032 about 3.5-fold higher in P-glycoprotein knockout mice than in wildtype mice, providing evidence of BMS-387032 being a P-glycoprotein substrate. Conclusions: Poor absorption may be playing a greater role than extensive first-pass metab. in the incomplete oral bioavailability of BMS-387032 seen in rats. The efflux transporter, P-glycoprotein, may be responsible for limiting absorption, as BMS-387032 appears to be a substrate of P-glycoprotein.
- 160Wyatt, P. G.; Woodhead, A. J.; Berdini, V.; Boulstridge, J. A.; Carr, M. G.; Cross, D. M.; Davis, D. J.; Devine, L. A.; Early, T. R.; Feltell, R. E.; Lewis, E. J.; McMenamin, R. L.; Navarro, E. F.; O’Brien, M. A.; O’Reilly, M.; Reule, M.; Saxty, G.; Seavers, L. C.; Smith, D. M.; Squires, M. S.; Trewartha, G.; Walker, M. T.; Woolford, A. J. Identification of N-(4-piperidinyl)-4-(2,6-dichlorbenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design J. Med. Chem. 2008, 51, 4986– 4999 DOI: 10.1021/jm800382h
- 161Cihalova, D.; Staud, F.; Ceckova, M. Interactions of cyclin-dependent kinase inhibitors AT-7519, flavopiridol and SNS-032 with ABCB1, ABCG2 and ABCC1 trasporters and their potential to overcome multidrug resistance in vitro Cancer Chemother. Pharmacol. 2015, 76, 105– 116 DOI: 10.1007/s00280-015-2772-1[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXos1Omsbc%253D&md5=3e8dcf19798145ffa656fc88dd2806d4Interactions of cyclin-dependent kinase inhibitors AT-7519, flavopiridol and SNS-032 with ABCB1, ABCG2 and ABCC1 transporters and their potential to overcome multidrug resistance in vitroCihalova, Daniela; Staud, Frantisek; Ceckova, MartinaCancer Chemotherapy and Pharmacology (2015), 76 (1), 105-116CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose: ATP-binding cassette (ABC) transporters play an important role in multidrug resistance (MDR) toward anticancer drugs. Here, we evaluated interactions of cyclin-dependent kinase inhibitors (CDKi) AT-7519, flavopiridol and SNS-032 with the following ABC transporters in vitro: P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-assocd. protein 1 (ABCC1). Methods: Inhibitory potency of studied CDKi to the transporters was evaluated by accumulation assays using fluorescent substrates and MDCKII cells overexpressing human ABCB1, ABCG2 or ABCC1. Resistance of transporter-expressing cells to the CDKi was evaluated by XTT proliferation assay. Obsd. interactions of CDKi were verified by ATPase assay in ABC transporter-expressing Sf9 membrane vesicles. Combination index anal. was addnl. performed in ABC transporter-expressing cancer cell lines, HepG2 and T47D. Results: Flavopiridol showed a significant inhibitory potency toward ABCG2 and ABCC1. SNS-032 also decreased ABCG2-mediated efflux, while AT-7519 failed to inhibit ABCB1, ABCG2 or ABCC1. Both flavopiridol and SNS-032 showed synergistic antiproliferative effects in combination with relevant ABC transporter substrates such as daunorubicin and topotecan in cancer cells. ABCB1 was found to confer significant resistance to AT-7519 and SNS-032, but not to flavopiridol. In contrast, ABCG2 and ABCC1 conferred resistance to flavopiridol, but not to AT-7519 and SNS-032. Conclusion: Our data provide detailed information on interactions of flavopiridol, SNS-032 and AT-7519 with ABC transporters, which may help elucidate the pharmacokinetic behavior and toxicity of these compds. Moreover, we show the ability of flavopiridol and SNS-032, but not AT-7519, to overcome ABC transporter-mediated MDR.
- 162Chu, X. J.; DePinto, W.; Bartkovitz, D.; So, S. S.; Vu, B. T.; Packman, K.; Lukacs, C.; Ding, Q.; Jiang, N.; Wang, K.; Goelzer, P.; Yin, X.; Smith, M. A.; Higgins, B. X.; Chen, Y.; Xiang, Q.; Moliterni, J.; Kaplan, G.; Graves, B.; Lovey, A.; Fotouhi, N. Discovery of [4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6-methoxyphenyl)methanone (R547), a potent and selective cyclin-dependent kinase inhibitor with significant in vivo antitumor activity J. Med. Chem. 2006, 49, 6549– 6560 DOI: 10.1021/jm0606138
- 163Byth, K. F.; Thomas, A.; Hughes, G.; Forder, C.; McGregor, A.; Geh, C.; Oakes, S.; Green, C.; Walker, M.; Newcombe, N.; Green, S.; Growcott, J.; Barker, A.; Wilkinson, R. W. AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts Mol. Cancer Ther. 2009, 8, 1856– 1866 DOI: 10.1158/1535-7163.MCT-08-0836[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosVyms70%253D&md5=2178bb1e046b382d71b846cce4644e35AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenograftsByth, Kate F.; Thomas, Andrew; Hughes, Gareth; Forder, Cheryl; McGregor, Alexandra; Geh, Catherine; Oakes, Sandra; Green, Clive; Walker, Mike; Newcombe, Nicholas; Green, Stephen; Growcott, Jim; Barker, Andy; Wilkinson, Robert W.Molecular Cancer Therapeutics (2009), 8 (7), 1856-1866CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Deregulation of the cell cycle has long been recognized as an essential driver of tumorigenesis, and agents that selectively target key cell cycle components continue to hold promise as potential therapeutics. We have developed AZD5438, a 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-methylsulfonylanilino) pyrimidine, as a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9 (IC50, 16, 6, and 20 nmol/L, resp.). In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC50 range, 0.2-1.7 μmol/L), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II C-terminal domain and blocking cell cycling at G2-M, S, and G1 phases. In vivo, when orally administered at either 50 mg/kg twice daily or 75 mg/kg once daily, AZD5438 inhibited human tumor xenograft growth (max. percentage tumor growth inhibition, range, 38-153; P < 0.05). In vivo, AZD5438 reduced the proportion of actively cycling cells. Further pharmacodynamic anal. of AZD5438-treated SW620 xenografts showed that efficacious doses of AZD5438 (>40% tumor growth inhibition) maintained suppression of biomarkers, such as phospho-pRbSer249/Thr252, for up to 16 h following a single oral dose. A comparison of different schedules indicated that chronic daily oral dosing provided optimal cover to ensure antitumor efficacy. These data indicate that broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has the pharmacol. profile that provides an ideal probe to test this premise. [Mol Cancer Ther 2009;8(7):1856-66].
- 164Zhang, I.; Zaorsky, N. G.; Palmer, J. D.; Mehra, R.; Lu, B. Targeting brain metastases in ALK-rearranged non-small-cell lung cancer Lancet Oncol. 2015, 16, e510– e521 DOI: 10.1016/S1470-2045(15)00013-3
- 165Cui, J. J.; Tran-Dube, M.; Shen, H.; Nambu, M.; Kung, P.; Pairish, M.; Jia, L.; Meng, J.; Funk, L.; Botrous, I.; McTigue, M.; Grodsky, N.; Ryan, K.; Padrique, E.; Alton, G.; Timofeevski, S.; Yamazaki, S.; Li, Q.; Zou, H.; Christensen, J.; Mroczkowski, B.; Bender, S.; Kania, R. S.; Edwards, M. P. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK) J. Med. Chem. 2011, 54, 6342– 6363 DOI: 10.1021/jm2007613[ACS Full Text], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVegtLrN&md5=dbab4c1b3e7c76180dbad04be2b6a474Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK)Cui, J. Jean; Tran-Dube, Michelle; Shen, Hong; Nambu, Mitchell; Kung, Pei-Pei; Pairish, Mason; Jia, Lei; Meng, Jerry; Funk, Lee; Botrous, Iriny; McTigue, Michele; Grodsky, Neil; Ryan, Kevin; Padrique, Ellen; Alton, Gordon; Timofeevski, Sergei; Yamazaki, Shinji; Li, Qiuhua; Zou, Helen; Christensen, James; Mroczkowski, Barbara; Bender, Steve; Kania, Robert S.; Edwards, Martin P.Journal of Medicinal Chemistry (2011), 54 (18), 6342-6363CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Because of the crit. roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncol. targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clin. candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.
- 166Camidge, D. R.; Bang, Y.-J.; Kwak, E. L.; Iafrate, A. J.; Varella-Garcia, M.; Fox, S. B.; Riely, G. J.; Solomon, B.; Ou, S.-H. I.; Kim, D.-W.; Salgia, R.; Fidias, P.; Engelman, J. A.; Gandhi, L.; Janne, P. A.; Costa, D. B.; Shapiro, G. I.; LoRusso, P.; Ruffner, K.; Stephenson, P.; Tang, Y.; Wilner, K.; Clark, J. W.; Shaw, A. T. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study Lancet Oncol. 2012, 13, 1011– 1019 DOI: 10.1016/S1470-2045(12)70344-3[Crossref], [PubMed], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVCjsb3E&md5=bd3aec44b197ee2f4c9d49ea540a672fActivity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 studyCamidge, D. Ross; Bang, Yung-Jue; Kwak, Eunice L.; Iafrate, A. John; Varella-Garcia, Marileila; Fox, Stephen B.; Riely, Gregory J.; Solomon, Benjamin; Ou, Sai-Hong I.; Kim, Dong-Wan; Salgia, Ravi; Fidias, Panagiotis; Engelman, Jeffrey A.; Gandhi, Leena; Jaenne, Pasi A.; Costa, Daniel B.; Shapiro, Geoffrey I.; LoRusso, Patricia; Ruffner, Katherine; Stephenson, Patricia; Tang, Yiyun; Wilner, Keith; Clark, Jeffrey W.; Shaw, Alice T.Lancet Oncology (2012), 13 (10), 1011-1019CODEN: LOANBN; ISSN:1470-2045. (Elsevier Ltd.)Summary: Background: ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. Methods: In this phase 1 study, patients with ALK-pos. stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumor responses, duration of response, time to tumor response, progression-free survival (PFS), overall survival at 6 and 12 mo, and detn. of the safety and tolerability and characterization of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analyzed in evaluable patients and PFS and safety were analyzed in all patients. This study is registered with ClinicalTrials.gov, no. NCT00585195. Findings: Between Aug 27, 2008, and June 1, 2011, 149 ALK-pos. patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3-68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 wk (range 2·1-39·6) and median duration of response was 49·1 wk (95% CI 39·3-75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 mo (95% CI 7·7-12·8). Median overall survival data are not yet mature, but estd. overall survival at 6 and 12 mo was 87·9% (95% CI 81·3-92·3) and 74·8% (66·4-81·5), resp. 39 patients continued to receive crizotinib for more than 2 wk after progression because of perceived ongoing clin. benefit from the drug (12 for at least 6 mo from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral edema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphatemia (n=6), and lymphopenia (n=6). Interpretation: Crizotinib is well tolerated with rapid, durable responses in patients with ALK-pos. NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed. Funding: Pfizer.
- 167Otterson, G. A.; Riely, G. J.; Shaw, A. T.; Crino, L.; Kim, D.-W.; Marins, R.; Salgia, R.; Zhou, C.; Solomon, B. J.; Wilner, K. D.; Polli, A.; Tang, Y.; Bartlett, C. H.; Ou, S.-H. I. Clinical characteristics of ALK+ NSCLC patients treated with crizotnib beyond disease progression: potential implications for management J. Clin. Oncol. 2012, 30 (Suppl.) 7600
- 168Costa, D. B.; Kobayashi, S.; Pandya, S. S.; Yeo, W.-L.; Shen, Z.; Tan, W.; Wilner, K. D. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib J. Clin. Oncol. 2011, 29, e443– 445 DOI: 10.1200/JCO.2010.34.1313
- 169Johnson, T. W.; Richardson, P. F.; Bailey, S.; Brooun, A.; Burke, B. J.; Collins, M. R.; Cui, J. J.; Deal, J. G.; Deng, Y.-L.; Dinh, D.; Engstrom, L. D.; He, M.; Hoffman, J.; Hoffman, R. L.; Huang, Q.; Kania, R. S.; Kath, J. C.; Lam, H.; Lam, J. L.; Le, P. T.; Lingardo, L.; Liu, W.; McTigue, M.; Palmer, C. L.; Sach, N. W.; Smeal, T.; Smith, G. L.; Stewart, A. E.; Timofeevski, S.; Zhu, H.; Zhu, J.; Zou, H. Y.; Edwards, M. P. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations J. Med. Chem. 2014, 57, 4720– 4744 DOI: 10.1021/jm500261q
- 170Awad, M. M.; Shaw, A. T. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond Clin. Adv. Hematol. Oncol. 2014, 12, 429– 439[PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M3htl2qug%253D%253D&md5=ae4655774258c9265a283749559ac393ALK inhibitors in non-small cell lung cancer: crizotinib and beyondAwad Mark M; Shaw Alice TClinical advances in hematology & oncology : H&O (2014), 12 (7), 429-39 ISSN:1543-0790.The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years, a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC, including ceritinib (LDK378), alectinib (RO5424802/CH5424802), AP26113, ASP3026, TSR-011, PF-06463922, RXDX-101, X-396, and CEP-37440. Cancers harboring ALK rearrangements may also be susceptible to treatment with heat shock protein 90 inhibitors. This review focuses on the pharmacologic and clinical properties of these compounds, either as monotherapies or in combination with other drugs. With so many ALK inhibitors in development, the challenges of how these agents should be studied and ultimately prescribed are also discussed.
- 171Marsilje, T. H.; Pei, W.; Chen, B.; Lu, W.; Uno, T.; Jin, Y.; Jiang, T.; Kim, S.; Li, N.; Warmuth, M.; Sarkisova, Y.; Sun, F.; Steffy, A.; Pferdekamper, A. C.; Li, A. G.; Joseph, S. B.; Kim, Y.; Liu, B.; Tuntland, T.; Cui, X.; Gray, N. S.; Steensma, R.; Wan, Y.; Jiang, J.; Chopiuk, G.; Li, J.; Gordon, W. P.; Richmond, W.; Johnson, K.; Chang, J.; Groessl, T.; He, Y.-Q.; Phimister, A.; Aycinena, A.; Lee, C. C.; Bursulaya, B.; Karanewsky, D. S.; Seidel, H. M.; Harris, J. L.; Michellys, P.-Y. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials J. Med. Chem. 2013, 56, 5675– 5690 DOI: 10.1021/jm400402q[ACS Full Text], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptVWjs7g%253D&md5=4b8f66e4acb27efe814956d7d0016068Synthesis, Structure-Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical TrialsMarsilje, Thomas H.; Pei, Wei; Chen, Bei; Lu, Wenshuo; Uno, Tetsuo; Jin, Yunho; Jiang, Tao; Kim, Sungjoon; Li, Nanxin; Warmuth, Markus; Sarkisova, Yelena; Sun, Frank; Steffy, Auzon; Pferdekamper, AnneMarie C.; Li, Allen G.; Joseph, Sean B.; Kim, Young; Liu, Bo; Tuntland, Tove; Cui, Xiaoming; Gray, Nathanael S.; Steensma, Ruo; Wan, Yongqin; Jiang, Jiqing; Chopiuk, Greg; Li, Jie; Gordon, W. Perry; Richmond, Wendy; Johnson, Kevin; Chang, Jonathan; Groessl, Todd; He, You-Qun; Phimister, Andrew; Aycinena, Alex; Lee, Christian C.; Bursulaya, Badry; Karanewsky, Donald S.; Seidel, H. Martin; Harris, Jennifer L.; Michellys, Pierre-YvesJournal of Medicinal Chemistry (2013), 56 (14), 5675-5690CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis, preclin. profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor (I; LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor (II; TAE684). Compd. I is currently in phase 1 and phase 2 clin. trials with substantial antitumor activity being obsd. in ALK-pos. cancer patients.
- 172(a) Shaw, A. T.; Kim, D. W.; Mehra, R.; Tan, D. S. W.; Felip, E.; Chow, L. Q. M.; Camidge, D. R.; Vansteenkiste, J.; Sharma, S.; De Pas, T.; Riely, G. J.; Solomon, B. J.; Wolf, J.; Thomas, M.; Schuler, M.; Liu, G.; Santoro, A.; Lau, Y. Y.; Goldwasser, M.; Boral, A. L.; Engelman, J. A. Ceritinib in ALK-rearranged non-small-cell lung cancer N. Engl. J. Med. 2014, 370, 1189– 1197 DOI: 10.1056/NEJMoa1311107[Crossref], [PubMed], [CAS], Google Scholar172ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlvVCitL0%253D&md5=dff3054469948ceb26a00e3eccac56c1Ceritinib in ALK-rearranged non-small-cell lung cancerShaw, Alice T.; Kim, Dong-Wan; Mehra, Ranee; Tan, Daniel S. W.; Felip, Enriqueta; Chow, Laura Q. M.; Camidge, Ross; Vansteenkiste, Johan; Sharma, Sunil; De Pas, Tommaso; Riely, Gregory J.; Solomon, Benjamin J.; Wolf, Juergen; Thomas, Michael; Schuler, Martin; Liu, Geoffrey; Santoro, Armando; Lau, Yvonne Y.; Goldwasser, Meredith; Boral, Anthony L.; Engelman, Jeffrey A.New England Journal of Medicine (2014), 370 (13), 1189-1197CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)Background: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclin. studies. Methods: In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the max. tolerated dose. Patients were assessed to det. the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. Results: A total of 59 patients were enrolled in the dose-escalation phase. The max. tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an addnl. 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were obsd. in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 mo (95% CI, 5.6 to 9.5). Conclusions: Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK.(b) Kim, D.-W.; Mehra, R.; Tan, D. S.-W.; Felip, E.; Chow, L. Q. M.; Camidge, D. R.; Vansteenkiste, J. F.; Sharma, S.; De Pas, T.; Riely, G. J.; Solomon, B. J.; Wolf, J.; Thomas, M.; Schuler, M. H.; Liu, G.; Santoro, A.; Geraldes, M.; Boral, A.; Yovine, A. J.; Shaw, A. T. Ceritinib in advanced anaplastic lymphoma (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): results of the ASCEND-1 trial J. Clin. Oncol. 2014, 32 (Suppl.) 8003(c) Shaw, A.; Mehra, R.; Tan, D. S. W.; Felip, E.; Chow, L. Q.; Camidge, D. R.; Vansteenkiste, J. R.; Sharma, S.; De Pas, T.; Riely, G. J.; Solomon, B.; Wolf, J.; Thomas, M.; Schuler, M.; Liu, G.; Santoro, A.; Geraldes, M.; Boral, A. L.; Yovine, A.; Kim, D. Evaluation of ceritinib-treated patients (pts) with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) and brain metastases in the ASCEND-1 Study Ann. Oncol. 2014, 25 (Suppl. 4) iv455– iv456
- 173Kinoshita, K.; Asoh, K.; Furuichi, N.; Ito, T.; Kawada, H.; Hara, S.; Ohwada, J.; Miyagi, T.; Kobayashi, T.; Takanashi, K.; Tsukaguchi, T.; Sakamoto, H.; Tsukuda, T.; Oikawa, N. Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802) Bioorg. Med. Chem. 2012, 20, 1271– 1280 DOI: 10.1016/j.bmc.2011.12.021[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFSmu70%253D&md5=cff263d2dd8c66de9fd687530fdadb06Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802)Kinoshita, Kazutomo; Asoh, Kohsuke; Furuichi, Noriyuki; Ito, Toshiya; Kawada, Hatsuo; Hara, Sousuke; Ohwada, Jun; Miyagi, Takuho; Kobayashi, Takamitsu; Takanashi, Kenji; Tsukaguchi, Toshiyuki; Sakamoto, Hiroshi; Tsukuda, Takuo; Oikawa, NobuhiroBioorganic & Medicinal Chemistry (2012), 20 (3), 1271-1280CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, esp. non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clin. candidate.
- 174Kodama, T.; Hasegawa, M.; Takanashi, K.; Sakurai, Y.; Kondoh, O.; Sakamoto, H. Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases Cancer Chemother. Pharmacol. 2014, 74, 1023– 1028 DOI: 10.1007/s00280-014-2578-6[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFeju7%252FK&md5=19b3fa282fb58bf492714d39207edac6Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastasesKodama, Tatsushi; Hasegawa, Masami; Takanashi, Kenji; Sakurai, Yuji; Kondoh, Osamu; Sakamoto, HiroshiCancer Chemotherapy and Pharmacology (2014), 74 (5), 1023-1028CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose: The clin. efficacy of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been demonstrated in ALK fusion-pos. non-small cell lung cancer (NSCLC); however, brain metastases are frequent sites of initial failure in patients due to poor penetration of the central nervous system by crizotinib. Here, we examd. the efficacy of a selective ALK inhibitor alectinib/CH5424802 in preclin. models of intracranial tumors. Methods: We established intracranial tumor implantation mouse models of EML4-ALK-pos. NSCLC NCI-H2228 and examd. the antitumor activity of alectinib in this model. Plasma distribution and brain distribution of alectinib were examd. by quant. whole-body autoradiog. administrating a single oral dose of 14C-labeled alectinib to rats. The drug permeability of alectinib was evaluated in Caco-2 cell. Results: Alectinib resulted in regression of NCI-H2228 tumor in mouse brain and provided a survival benefit. In a pharmacokinetic study using rats, alectinib showed a high brain-to-plasma ratio, and in an in vitro drug permeability study using Caco-2 cells, alectinib was not transported by P-glycoprotein efflux transporter that is a key factor in blood-brain barrier penetration. Conclusions: We established intracranial tumor implantation models of EML4-ALK-pos. NSCLC. Alectinib showed potent efficacy against intracranial EML4-ALK-pos. tumor. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with brain metastases.
- 175(a) Gadgeel, S. M.; Gandhi, L.; Riely, G. J.; Chiappori, A. A.; West, H. L.; Azada, M. C.; Morcos, P. N.; Lee, R.-M.; Garcia, L.; Yu, L.; Boisserie, F.; Di Laurenzio, L.; Golding, S.; Sato, J.; Yokoyama, S.; Tanaka, T.; Ou, S.-H. I. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study Lancet Oncol. 2014, 15, 1119– 1128 DOI: 10.1016/S1470-2045(14)70362-6[Crossref], [PubMed], [CAS], Google Scholar175ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVSmt77K&md5=aa56d295472ea5dcb29070a4e39d420aSafety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 studyGadgeel, Shirish M.; Gandhi, Leena; Riely, Gregory J.; Chiappori, Alberto A.; West, Howard L.; Azada, Michele C.; Morcos, Peter N.; Lee, Ruey-Min; Garcia, Linta; Yu, Li; Boisserie, Frederic; Di Laurenzio, Laura; Golding, Sophie; Sato, Jotaro; Yokoyama, Shumpei; Tanaka, Tomohiro; Ou, Sai-Hong IgnatiusLancet Oncology (2014), 15 (10), 1119-1128CODEN: LOANBN; ISSN:1470-2045. (Elsevier Ltd.)Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progression-free survival of 8-11 mo while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clin. activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib. We enrolled patients with ALK-rearranged NSCLC who progressed on or were intolerant to crizotinib. We administered various oral doses of alectinib (300-900 mg twice a day) during the dose-escalation portion of the study (phase 1), to ascertain the recommended dose for phase 2. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.1) to investigate the activity of alectinib in all patients with a baseline scan and at least one post-treatment scan (CT or MRI), with central radiol. review of individuals with brain metastases. We assessed safety in all patients who received at least one dose of alectinib. Here, we present data for the phase 1 portion of the study, the primary objective of which was to establish the recommended phase 2 dose; phase 2 is ongoing. This trial is registered at ClinicalTrials.gov, no. NCT01588028.47 patients were enrolled. Alectinib was well tolerated, with the most common adverse events being fatigue (14 [30%]; all grade 1-2), myalgia (eight [17%]; all grade 1-2), and peripheral edema (seven [15%] grade 1-2, one [2%] grade 3). Dose-limiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day; one individual had grade 3 headache and the other had grade 3 neutropenia. The most common grade 3-4 adverse events were increased levels of γ-glutamyl transpeptidase (two [4%]), a redn. in the no. of neutrophils (two [4%]), and hypophosphatemia (two [4%]). Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib: acute renal failure; pleural effusion and pericardial effusion; and brain metastasis. At data cut-off (median follow-up 126 days [IQR 84-217]), 44 patients could be assessed for activity. Investigator-assessed objective responses were noted in 24 (55%) patients, with a confirmed complete response in one (2%), a confirmed partial response in 14 (32%), and an unconfirmed partial response in nine (20%). 16 (36%) patients had stable disease; the remaining four (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had an objective response; six (29%) had a complete response (three unconfirmed) and five (24%) had a partial response (one unconfirmed); eight (38%) patients had stable disease and the remaining two (10%) had progressive disease. Pharmacokinetic data indicated that mean exposure (AUC0-10) after multiple doses of alectinib (300-600 mg twice a day) was dose-dependent. Alectinib was well tolerated, with promising antitumor activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2. Chugai Pharmaceuticals, F Hoffmann La-Roche.(b) Ajimizu, H.; Kim, Y. H.; Mishima, M. Rapid response of brain metastases to alectinib in a patient with non-small-cell lung cancer resistant to crizotinib Med. Oncol. 2015, 32, 3 DOI: 10.1007/s12032-014-0477-7(c) Gainor, J. F.; Sherman, C. A.; Willoughby, K.; Logan, J.; Kennedy, E.; Brastianos, P. K.; Chi, A. S.; Shaw, A. T. Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib J. Thorac. Oncol. 2015, 10, 232– 236 DOI: 10.1097/JTO.0000000000000455[Crossref], [PubMed], [CAS], Google Scholar175chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVentLY%253D&md5=02a74597e914c4472f8d4d7edc128ba1Alectinib Salvages CNS Relapses in ALK-Positive Lung Cancer Patients Previously Treated with Crizotinib and CeritinibGainor, Justin F.; Sherman, Carol A.; Willoughby, Kathryn; Logan, Jennifer; Kennedy, Elizabeth; Brastianos, Priscilla K.; Chi, Andrew S.; Shaw, Alice T.Journal of Thoracic Oncology (2015), 10 (2), 232-236CODEN: JTOOB7; ISSN:1556-0864. (Lippincott Williams & Wilkins)Background: Leptomeningeal metastases (LM) are an increasingly frequent and devastating complication of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). Currently, the optimal management of LM in ALK-pos. patients remains poorly understood as these patients have been routinely excluded from clin. trials. Methods: We describe four ALK-pos. patients with LM who were treated with the next-generation ALK inhibitor alectinib through single-patient, compassionate use protocols at two institutions. All patients had previously been treated with both FDA-approved ALK inhibitors-crizotinib and ceritinib. Patients received alectinib at a starting dose of 600 mg twice daily. Results: Four ALK-pos. NSCLC patients with symptomatic leptomeningeal disease were identified. Three of four patients experienced significant clin. and radiog. improvements in LM upon treatment with alectinib. A fourth patient had stable intracranial disease for 4 mo before eventual systemic disease progression. Overall, alectinib was well tolerated. One patient required dose redn. due to grade 2 hyperbilirubinemia. Conclusions: Alectinib is active in ALK-rearranged NSCLC patients with LM, including in patients previously treated with crizotinib and ceritinib. Addnl. prospective studies of alectinib in ALK-pos. patients with LM are warranted.
- 176Menichincheri, M.; Ardini, E.; Magnaghi, P.; Avanzi, N.; Banfi, P.; Bossi, R.; Buffa, L.; Canevari, G.; Ceriani, L.; Colombo, M.; Corti, L.; Donati, D.; Fasolini, M.; Felder, E.; Fiorelli, C.; Fiorentini, F.; Galvani, A.; Isacchi, A.; Borgia, A. L.; Marchionni, C.; Nesi, M.; Orrenius, C.; Panzeri, A.; Pesenti, E.; Rusconi, L.; Saccardo, M. B.; Vanotti, E.; Perrone, E.; Orsini, P. Discovery of entrectinib: a new 3-aminoindazole as a potent anaplastic lymphoma kinase (ALK), c-ros oncogene 1 kinase (ROS1), and pan-tropomyosin receptor kinases (pan-TRKs) inhibitor J. Med. Chem. 2016, 59, 3392– 3408 DOI: 10.1021/acs.jmedchem.6b00064[ACS Full Text], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xks1eitL8%253D&md5=140217fba2ac81d71600f7344f2d8a3eDiscovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitorMenichincheri, Maria; Ardini, Elena; Magnaghi, Paola; Avanzi, Nilla; Banfi, Patrizia; Bossi, Roberto; Buffa, Laura; Canevari, Giulia; Ceriani, Lucio; Colombo, Maristella; Corti, Luca; Donati, Daniele; Fasolini, Marina; Felder, Eduard; Fiorelli, Claudio; Fiorentini, Francesco; Galvani, Arturo; Isacchi, Antonella; Borgia, Andrea Lombardi; Marchionni, Chiara; Nesi, Marcella; Orrenius, Christian; Panzeri, Achille; Pesenti, Enrico; Rusconi, Luisa; Saccardo, Maria Beatrice; Vanotti, Ermes; Perrone, Ettore; Orsini, PaoloJournal of Medicinal Chemistry (2016), 59 (7), 3392-3408CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clin. activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within the ALK drug discovery program, the authors identified compd. I, a novel 3-aminoindazole active on ALK in biochem. and in cellular assays. Its optimization led to compd. II (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clin. trial for the treatment of patients affected by ALK-, ROS1-, and TRK-pos. tumors.
- 177Farago, A. F.; Le, L. P.; Zheng, Z.; Muzikansky, A.; Drilon, A.; Patel, M.; Bauer, T. M.; Liu, S. V.; Ou, S. I.; Jackman, D.; Costa, D. B.; Multani, P. S.; Li, G. G.; Hornby, Z.; Chow-Maneval, E.; Luo, D.; Lim, J. E.; Iafrate, A. J.; Shaw, A. T. Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer J. Thorac. Oncol. 2015, 10, 1670– 1674 DOI: 10.1097/01.JTO.0000473485.38553.f0[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvF2it7rN&md5=1d0160c35a3bdbdcb2ebd01313cc18baDurable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung CancerFarago, Anna F.; Le, Long P.; Zheng, Zongli; Muzikansky, Alona; Drilon, Alexander; Patel, Manish; Bauer, Todd M.; Liu, Stephen V.; Ou, Sai-Hong I.; Jackman, David; Costa, Daniel B.; Multani, Pratik S.; Li, Gary G.; Hornby, Zachary; Chow-Maneval, Edna; Luo, David; Lim, Jonathan E.; Iafrate, Anthony J.; Shaw, Alice T.Journal of Thoracic Oncology (2015), 10 (12), 1670-1674CODEN: JTOOB7; ISSN:1556-0864. (Lippincott Williams & Wilkins)Introduction: Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to det. the frequency of NTRK1 rearrangements in NSCLC and to assess the clin. activity of entrectinib. Methods: We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment. Results: We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3-4 adverse events. Within three weeks of starting on treatment, the patient reported resoln. of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resoln. of all brain metastases. This patient has continued on treatment for over 6 mo with an ongoing PR. Conclusions: Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.
- 178Mori, M.; Ueno, Y.; Konagai, S.; Fushiki, H.; Shimada, I.; Kondoh, Y.; Saito, R.; Mori, K.; Shindou, N.; Soga, T.; Sakagami, H.; Furutani, T.; Doihara, H.; Kudoh, M.; Kuromitsu, S. The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs survival in non-small cell lung cancer model mice Mol. Cancer Ther. 2014, 13, 329– 340 DOI: 10.1158/1535-7163.MCT-13-0395[Crossref], [PubMed], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFWmsb8%253D&md5=4d8de3814f3f8fa198f2d3acb5d3860aThe Selective Anaplastic Lymphoma Receptor Tyrosine Kinase Inhibitor ASP3026 Induces Tumor Regression and Prolongs Survival in Non-Small Cell Lung Cancer Model MiceMori, Masamichi; Ueno, Yoko; Konagai, Satoshi; Fushiki, Hiroshi; Shimada, Itsuro; Kondoh, Yutaka; Saito, Rika; Mori, Kenichi; Shindou, Nobuaki; Soga, Takatoshi; Sakagami, Hideki; Furutani, Takashi; Doihara, Hitoshi; Kudoh, Masafumi; Kuromitsu, SadaoMolecular Cancer Therapeutics (2014), 13 (2), 329-340CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Activation of anaplastic lymphoma receptor tyrosine kinase (ALK) is involved in the pathogenesis of several carcinomas, including non-small cell lung cancer (NSCLC). Echinoderm microtubule-assocd. protein like 4 (EML4)-ALK, which is derived from the rearrangement of ALK and EML4 genes, has been validated as a therapeutic target in a subset of patients with NSCLC. Here, we investigated the effects of ASP3026, a novel small-mol. ALK inhibitor, against ALK-driven NSCLC. ASP3026 inhibited ALK activity in an ATP-competitive manner and had an inhibitory spectrum that differed from that of crizotinib, a dual ALK/MET inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, orally administered ASP3026 was well absorbed in tumor tissues, reaching concns. >10-fold higher than those in plasma, and induced tumor regression with a wide therapeutic margin between efficacious and toxic doses. In the same mouse model, ASP3026 enhanced the antitumor activities of paclitaxel and pemetrexed without affecting body wt. ASP3026 also showed potent antitumor activities, including tumor shrinkage to a nondetectable level, in hEML4-ALK transgenic mice and prolonged survival in mice with intrapleural NCI-H2228 xenografts. In an intrahepatic xenograft model using NCI-H2228 cells, ASP3026 induced continuous tumor regression, whereas mice treated with crizotinib showed tumor relapse after an initial response. Finally, ASP3026 exhibited potent antitumor activity against cells expressing EML4-ALK with a mutation in the gatekeeper position (L1196M) that confers crizotinib resistance. Taken together, these findings indicate that ASP3026 has potential efficacy for NSCLC and is expected to improve the therapeutic outcomes of patients with cancer with ALK abnormality. Mol Cancer Ther; 13(2); 329-40. ©2014 AACR.
- 179Fushiki, H.; Saito, R.; Jitsuoka, M.; Shimada, I.; Kondoh, Y.; Sakagami, H.; Funatsu, Y.; Noda, A.; Murakami, Y.; Miyoshi, S.; Ueon, Y.; Konagai, S.; Soga, T.; Nishimura, S.; Mori, M.; Kuromitsu, S. Abstract 2678: First demonstration of in vivo PET imaging for ALK inhibitor using [11C]ASP3026, a novel brain-permeable type of ALK inhibitor Cancer Res. 2013, 73 (Suppl.) 2678 DOI: 10.1158/1538-7445.AM2013-2678
- 180Huang, W. S.; Liu, S.; Zou, D.; Thomas, M.; Wang, Y.; Zhou, T.; Romero, J.; Kohlmann, A.; Li, F.; Qi, J.; Cai, L.; Dwight, T. A.; Xu, Y.; Xu, R.; Dodd, R.; Toms, A.; Parillon, L.; Lu, X.; Anjum, R.; Zhang, S.; Wang, F.; Keats, J.; Wardwell, S. D.; Ning, Y.; Xu, Q.; Moran, L. E.; Mohemmad, Q. K.; Jang, H. G.; Clackson, T.; Narashimhan, N. I.; Rivera, V. M.; Zhu, X.; Dalgarno, D.; Shakespeare, W. C. Discovery of brigatinib (AP26113), a phosphine oxide-containing, potent, orally active inhibitor of analplastic lymphoma kinase J. Med. Chem. 2016, 59, 4948– 4964 DOI: 10.1021/acs.jmedchem.6b00306
- 181Gettinger, S. N.; Bazhenova, L.; Salgia, R.; Langer, C. J.; Gold, K. A.; Rosell, R.; Shaw, A. T.; Weiss, G. J.; Narasimhan, N. I.; Dorer, D. J.; Rivera, V. M.; Clackson, T.; Haluska, F. G.; Camidge, D. R. Updated efficacy and safety of the ALK inhibitor AP26113 in patients with advanced malignancies, including ALK+ non-small cell lung cancer J. Thorac. Oncol. 2013, 8 (Suppl. 2) S296
- 182Camidge, D. R.; Bazhenova, L.; Salgia, R.; Langer, C. J.; Gold, K. A.; Rosell, R.; Shaw, A. T.; Weiss, G. J.; Narasimhan, N. I.; Dorer, D. J.; Rivera, V. M.; Clackson, T. P.; Conlan, M. G.; Kerstein, D.; Haluska, F. G.; Gettinger, S. N. Safety and efficacy of brigatinib (AP26113) in advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC) J. Clin. Oncol. 2015, 33 (Suppl.) 8062
- 183Lovly, C. M.; Heuckmann, J. M.; de Stanchina, E.; Chen, H.; Thomas, R. K.; Liang, C.; Pao, W. Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors Cancer Res. 2011, 71, 4920– 4931 DOI: 10.1158/0008-5472.CAN-10-3879[Crossref], [PubMed], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXovFartro%253D&md5=000cbd1295c9d9fa6a43027f08c31247Insights into ALK-Driven Cancers Revealed through Development of Novel ALK Tyrosine Kinase InhibitorsLovly, Christine M.; Heuckmann, Johannes M.; de Stanchina, Elisa; Chen, Heidi; Thomas, Roman K.; Liang, Chris; Pao, WilliamCancer Research (2011), 71 (14), 4920-4931CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers, where ALK represents a rational therapeutic target in these settings. In this study, we report the identification and biol. characterization of X-376 and X-396, two potent and highly specific ALK small mol. tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays, X-376 and X-396 were more potent inhibitors of ALK but less potent inhibitors of MET compared to PF-02341066 (PF-1066), an ALK/MET dual TKI currently in clin. trials. Both X-376 and X-396 displayed potent antitumor activity in vivo with favorable pharmacokinetic and toxicity profiles. Similar levels of drug sensitivity were displayed by the three most common ALK fusion proteins in lung cancer (EML4-ALK variants E13;A20, E20;A20, and E6b;A20) as well as a KIF5B-ALK fusion protein. Moreover, X-396 could potently inhibit ALK kinases engineered with two point mutations assocd. with acquired resistance to PF-1066, L1196M, and C1156Y, when engineered into an E13;A20 fusion variant. Finally, X-396 displayed synergistic growth inhibitory activity when combined with the mTOR inhibitor rapamycin. Our findings offer preclin. proof-of-concept for use of these novel agents to improve therapeutic outcomes of patients with mutant ALK-driven malignancies. Cancer Res; 71(14); 4920-31.
- 184Lin, N. U.; Dieras, V.; Paul, D.; Lossignol, D.; Christodoulou, C.; Stemmler, H.-J.; Roche, H.; Liu, M. C.; Greil, R.; Ciruelos, E.; Loibl, S.; Gori, S.; Wardley, A.; Yardley, D.; Brufsky, A.; Blum, J. L.; Rubin, S. D.; Dharan, B.; Steplewski, K.; Zembryki, D.; Oliva, C.; Roychowdhury, D.; Paoletti, P.; Winer, E. P. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer Clin. Cancer Res. 2009, 15, 1452– 1459 DOI: 10.1158/1078-0432.CCR-08-1080[Crossref], [PubMed], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXitVOktLo%253D&md5=74b9997947af74996e9eb840a6ff9152Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast CancerLin, Nancy U.; Dieras, Veronique; Paul, Devchand; Lossignol, Dominique; Christodoulou, Christos; Stemmler, Hans-Joachim; Roche, Henri; Liu, Minetta C.; Greil, Richard; Ciruelos, Eva; Loibl, Sibylle; Gori, Stefania; Wardley, Andrew; Yardley, Denise; Brufsky, Adam; Blum, Joanne L.; Rubin, Stephen D.; Dharan, Bernie; Steplewski, Klaudia; Zembryki, Denise; Oliva, Cristina; Roychowdhury, Debasish; Paoletti, Paolo; Winer, Eric P.Clinical Cancer Research (2009), 15 (4), 1452-1459CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)PURPOSE: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clin. challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was assocd. with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. Exptl. Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as ≥50% volumetric redn. of CNS lesion(s) in the absence of increasing steroid use, progressive neurol. signs and symptoms, or progressive extra-CNS disease. RESULTS: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were obsd. in 6% of patients. In an exploratory anal., 21% of patients experienced a ≥20% volumetric redn. in their CNS lesions. An assocn. was obsd. between volumetric redn. and improvement in progression-free survival and neurol. signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a ≥20% volumetric redn. in their CNS lesions. CONCLUSIONS: This study confirms the modest CNS antitumor activity of lapatinib. Addnl. responses were obsd. with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.
- 185Medina, P. J.; Goodin, S. Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases Clin. Ther. 2008, 30, 1426– 1447 DOI: 10.1016/j.clinthera.2008.08.008[Crossref], [PubMed], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtF2rtLfL&md5=e2e7505d278f03060c4bf664994f1ae1Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinasesMedina, Patrick J.; Goodin, SusanClinical Therapeutics (2008), 30 (8), 1426-1447CODEN: CLTHDG; ISSN:0149-2918. (Excerpta Medica, Inc.)A review. Background: Lapatinib, the first dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, was approved by the US Food and Drug Administration (FDA) in 2007. It is indicated for use in combination with capecitabine for the treatment of patients with advanced breast cancer or metastatic breast cancer (MBC) whose tumors overexpress HER2 (ErbB2) and who have received previous treatment that included an anthracycline, a taxane, and trastuzumab. Objective: This review summarizes the pharmacol., pharmacokinetics, clin. efficacy, and safety profile of lapatinib, and its current and potential role in the treatment of breast cancer and other malignancies. Methods: Relevant English-language publications were identified through searches of MEDLINE (1966-May 2008), the American Society of Clin. Oncol. abstrs. database (2000-2007), abstrs. from the San Antonio Breast Cancer Symposium (2005-2007), and the FDA Web site (Jan. 2008). Search terms included lapatinib, GW572016, HER2, EGFR, receptor tyrosine kinase, dual-receptor blockade, adverse events, and clin. trials. Results: The Tmax of lapatinib after oral administration is 3 to 4 h. Dividing the dose or administering it with food, particularly a high-fat meal, increases the AUC >2-fold. Lapatinib is metabolized primarily by the cytochrome P 450 3A4 isoenzyme, with 1 metabolite remaining active against EGFR but not HER2. Due to drug accumulation, the t1/2 of lapatinib is 24 h with continuous dosing. In a Phase III trial comparing lapatinib and capecitabine with capecitabine alone in women with HER2-pos., locally advanced breast cancer or MBC that had progressed after treatment with an anthracycline, a taxane, and trastuzumab, the combination of lapatinib and capecitabine was assocd. with a numeric improvement in response rate compared with capecitabine alone (22% vs 14%, resp.; P = NS) and a significant increase in time to progression (6.2 vs 4.3 mo; hazard ratio = 0.57; 95% CI, 0.43-0.77; P < 0.001). Lapatinib has been reported to have antitumor activity in Phase II trials when used as first-line therapy for MBC, in patients with inflammatory breast cancer, and in patients with central nervous system metastases. Phase II trials in other solid tumor types found modest activity. The approved dosing of lapatinib is 1250 mg PO QD given continuously in combination with capecitabine 2000 mg/m2 daily administered in 2 divided doses on days 1 to 14 of a 21-day cycle. The most common clin. toxicities of all grades assocd. with lapatinib used in combination with capecitabine in the pivotal clin. trial were diarrhea (65%), hand-foot syndrome (53%), nausea (44%), rash (29%), and fatigue (24%). Cardiac toxicity appears to be less frequent with lapatinib than with trastuzumab. Conclusions: Lapatinib is a dual inhibitor of the EGFR and HER2 tyrosine kinases. It is approved by the FDA for use in combination with capecitabine for the treatment of HER2-pos. MBC that has progressed with std. treatment. In clin. trials, this combination was assocd. with a significant improvement in the time to progression in patients with MBC. Lapatinib's efficacy in other malignancies that overexpress EGFR and/or HER2 is under evaluation.
- 186Taskar, K. S.; Rudraraju, V.; Mittapalli, R. K.; Samala, R.; Thorsheim, H. R.; Lockman, J.; Gril, B.; Hua, E.; Palmieri, D.; Polli, J. W.; Castellino, S.; Rubin, S. D.; Lockman, P. R.; Steeg, P. S.; Smith, Q. R. Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer Pharm. Res. 2012, 29, 770– 781 DOI: 10.1007/s11095-011-0601-8[Crossref], [PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtleqsLbN&md5=93de4680e8dcd3b0ee065ac002948ab7Lapatinib Distribution in HER2 Overexpressing Experimental Brain Metastases of Breast CancerTaskar, Kunal S.; Rudraraju, Vinay; Mittapalli, Rajendar K.; Samala, Ramakrishna; Thorsheim, Helen R.; Lockman, Julie; Gril, Brunilde; Hua, Emily; Palmieri, Diane; Polli, Joseph W.; Castellino, Stephen; Rubin, Stephen D.; Lockman, Paul R.; Steeg, Patricia S.; Smith, Quentin R.Pharmaceutical Research (2012), 29 (3), 770-781CODEN: PHREEB; ISSN:0724-8741. (Springer)Lapatinib, a small mol. EGFR/HER2 inhibitor, partially inhibits the outgrowth of HER2+ brain metastases in preclin. models and in a subset of CNS lesions in clin. trials of HER2+ breast cancer. We investigated the ability of lapatinib to reach therapeutic concns. in the CNS following 14C-lapatinib administration (100 mg/kg p.o. or 10 mg/kg, i.v.) to mice with MDA-MD-231-BR-HER2 brain metastases of breast cancer. Drug concns. were detd. at differing times after administration by quant. autoradiog. and chromatog. 14C-Lapatinib concn. varied among brain metastases and correlated with altered blood-tumor barrier permeability. On av., brain metastasis concn. was 7-9-fold greater than surrounding brain tissue at 2 and 12 h after oral administration. However, av. lapatinib concn. in brain metastases was still only 10-20% of those in peripheral metastases. Only in a subset of brain lesions (17%) did lapatinib concn. approach that of systemic metastases. No evidence was found of lapatinib resistance in tumor cells cultured ex vivo from treated brains. Results show that lapatinib distribution to brain metastases of breast cancer is partially restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies between tumors.
- 187Polli, J. W.; Olson, K. L.; Chism, J. P.; St. John-Williams, L.; Yeager, R. L.; Woodard, S. M.; Otto, V.; Castellino, S.; Demby, V. E. An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016 Drug Metab. Dispos. 2009, 37, 439– 442 DOI: 10.1124/dmd.108.024646
- 188Morikawa, A.; Peereboom, D. M.; Thorsheim, H. R.; Samala, R.; Balyan, R.; Murphy, C. G.; Lockman, P. R.; Simmons, A.; Weil, R. J.; Tabar, V.; Steeg, P. S.; Smith, Q. R.; Seidman, A. D. Capcitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study Neuro-Oncology 2015, 17, 289– 295 DOI: 10.1093/neuonc/nou141
- 189Schroeder, R. L.; Stevens, C. L.; Sridhar, J. Small molecule tyrosine kinase inhibitors of ErbB2/HER2/Neu in the treatment of aggressive breast cancer Molecules 2014, 19, 15196– 15212 DOI: 10.3390/molecules190915196[Crossref], [PubMed], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslSitLzF&md5=6b2f45be989c622b9a8d3dd7fd3f0146Small molecule tyrosine kinase inhibitors of ErbB2/HER2/Neu in the treatment of aggressive breast cancerSchroeder, Richard L.; Stevens, Cheryl L.; Sridhar, JayalakshmiMolecules (2014), 19 (9), 15196-15212, 17 pp.CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. The human epidermal growth factor receptor 2 (HER2) is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play crit. roles in the signal transduction cascade in a myriad of biochem. pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-pos. breast cancer. Existing therapies such as trastuzumab (Herceptin) and lapatinib (Tyverb/Tykerb), a monoclonal antibody inhibitor and a dual EGFR/HER2 kinase inhibitor, resp., are currently used in the treatment of HER2-pos. cancers, although issues with high recurrence and acquired resistance still remain. Small mol. tyrosine kinase inhibitors provide attractive therapeutic targets, as they are able to block cell signaling assocd. with many of the proposed mechanisms for HER2 resistance. In this regard we aim to present a review on the available HER2 tyrosine kinase inhibitors, as well as those currently in development. The use of tyrosine kinase inhibitors as sequential or combinatorial therapeutic strategies with other HER family inhibitors is also discussed.
- 190Feldinger, K.; Kong, A. Profile of neratinib and its potential in the treatment of breast cancer Breast Cancer: Targets Ther. 2015, 7, 147– 162 DOI: 10.2147/BCTT.S54414[Crossref], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnsFCht7c%253D&md5=599b49c22d664816005fc555b9ef3384Profile of neratinib and its potential in the treatment of breast cancerFeldinger, Katharina; Kong, AnthonyBreast Cancer: Targets and Therapy (2015), 7 (), 147-162CODEN: BCTTA9; ISSN:1179-1314. (Dove Medical Press Ltd.)The HER (ErbB) receptor tyrosine kinase receptors are implicated in many cancers and several anti-HER treatments are now approved. In recent years, a new group of compds. that bind irreversibly to the ATP binding pocket of HER receptors have been developed. One of these compds., neratinib, has passed preclin. phases and is currently undergoing various clin. trials. This manuscript reviews the preclin. as well as clin. data on neratinib. As a pan-HER inhibitor, this irreversible tyrosine kinase inhibitor binds and inhibits the tyrosine kinase activity of epidermal growth factor receptors, EGFR (or HER1), HER2 and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib has been shown to be effective against HER2-overexpressing or mutant tumors in vitro and in vivo. Neratinib is currently being investigated in various clin. trials in breast cancers and other solid tumors, including those with HER2 mutation. Earlier studies have already shown promising clin. activity for neratinib. However, more translational research is required to investigate biomarkers that could help to predict response and resistance for selection of appropriate patients for treatment with neratinib, either as monotherapy or in combination with other drug(s).
- 191Dinkel, V.; Anderson, D.; Winski, S.; Winkler, J.; Koch, K.; Lee, P. A. Abstract 852: ARRY-380, a potent, small molecule inhibitor of ErbB2, increases survival in intracranial ErbB2+ xenograft models in mice Cancer Res. 2012, 72 (Suppl.) 852 DOI: 10.1158/1538-7445.AM2012-852
- 192Freedman, R. A.; Gelman, R. S.; Wefel, J. S.; Melisko, M. E.; Hess, K. R.; Connolly, R. M.; Van Poznak, C. H.; Niravath, P. A.; Puhalla, S. L.; Ibrahim, N.; Blackwell, K. L.; Liu, M. C.; Lowe, A.; Agar, N. Y. R.; Ryabin, N.; Farooq, S.; Lawler, E.; Rimawi, M. F.; Krop, I. E.; Wolff, A. C.; Winer, E. P.; Lin, N. U. Translational Breast Cancer Research Consortium (TBCRC) 022: A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases J. Clin. Oncol. 2016, 34, 945– 952 DOI: 10.1200/JCO.2015.63.0343[Crossref], [PubMed], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28nmtlOgsA%253D%253D&md5=88dba0840a4214b2abf63bc4765c669eTranslational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain MetastasesFreedman Rachel A; Gelman Rebecca S; Wefel Jeffrey S; Melisko Michelle E; Hess Kenneth R; Connolly Roisin M; Van Poznak Catherine H; Niravath Polly A; Puhalla Shannon L; Ibrahim Nuhad; Blackwell Kimberly L; Moy Beverly; Herold Christina; Liu Minetta C; Lowe Alarice; Agar Nathalie Y R; Ryabin Nicole; Farooq Sarah; Lawler Elizabeth; Rimawi Mothaffar F; Krop Ian E; Wolff Antonio C; Winer Eric P; Lin Nancy UJournal of clinical oncology : official journal of the American Society of Clinical Oncology (2016), 34 (9), 945-52 ISSN:.PURPOSE: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. PATIENTS AND METHODS: Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders. RESULTS: Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. CONCLUSION: Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.
- 193Roche, S.; Pedersen, K.; Dunne, G.; Collins, D.; Devery, A.; Crown, J.; Clynes, M.; O’Connor, R. Pharmacological interactions of TKIs with the P-gp drug transport protein J. Clin. Oncol. 2012, 30 (Suppl.) 2536
- 194Metzger-Filho, O.; Barry, W. T.; Krop, I. E.; Younger, W. J.; Lawler, E. S.; Winer, E. P.; Lin, N. U. Phase I dose-escalation trial of ONT-380 in combination with trastuzumab in participants with brain metastases from HER2+ breast cancer J. Clin. Oncol. 2014, 32 (Suppl.) TPS660
- 195Ishikawa, T.; Seto, M.; Banno, H.; Kawakita, Y.; Oorui, M.; Taniguchi, T.; Ohta, Y.; Tamura, T.; Nakayama, A.; Miki, H.; Kamiguchi, H.; Tanaka, T.; Habuka, N.; Sogabe, S.; Yano, J.; Aertgeerts, K.; Kamiyama, K. Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold J. Med. Chem. 2011, 54, 8030– 8050 DOI: 10.1021/jm2008634[ACS Full Text], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlajur7M&md5=ce030ac133a1c0ff7cb78b269ff85987Design and Synthesis of Novel Human Epidermal Growth Factor Receptor 2 (HER2)/Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing a Pyrrolo[3,2-d]pyrimidine ScaffoldIshikawa, Tomoyasu; Seto, Masaki; Banno, Hiroshi; Kawakita, Youichi; Oorui, Mami; Taniguchi, Takahiko; Ohta, Yoshikazu; Tamura, Toshiya; Nakayama, Akiko; Miki, Hiroshi; Kamiguchi, Hidenori; Tanaka, Toshimasa; Habuka, Noriyuki; Sogabe, Satoshi; Yano, Jason; Aertgeerts, Kathleen; Kamiyama, KeijiJournal of Medicinal Chemistry (2011), 54 (23), 8030-8050CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivs., e.g. I, capable of fitting into the receptors' ATP binding site. Among the prepd. compds., I showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of I with both HER2 and EGFR demonstrated that I interacts with the expected residues in their resp. ATP pockets. Furthermore, reflecting its good oral bioavailability, I exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report I (TAK-285) as a promising candidate for clin. development as a novel HER2/EGFR dual kinase inhibitor.
- 196Erdo, F.; Gordon, J.; Wu, J. T.; Sziraki, I. Verification of brain penetration of the unbound fraction of a novel HER2/EGFR dual kinase inhibitor (TAK-285) by microdialysis in rats Brain Res. Bull. 2012, 87, 413– 419 DOI: 10.1016/j.brainresbull.2012.01.002[Crossref], [PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1Gqtrw%253D&md5=88acff4f029db2032dfae93bff601d18Verification of brain penetration of the unbound fraction of a novel HER2/EGFR dual kinase inhibitor (TAK-285) by microdialysis in ratsErdo, Franciska; Gordon, Justin; Wu, Jing-Tao; Sziraki, IstvanBrain Research Bulletin (2012), 87 (4-5), 413-419CODEN: BRBUDU; ISSN:0361-9230. (Elsevier Inc.)TAK-285, an investigational, orally active HER2/EGRF inhibitor is in clin. development for potential use in HER2 over-expressing metastatic breast cancer. The objective of the present work was to verify the presence of unbound TAK-285 in the rat brain after oral administration by a microdialysis technique with simultaneous sampling of blood and brain. In a pilot microdialysis expt. no detectable amt. of TAK-285 was found in the brain dialyzate samples after oral administration of the drug (50 mg/kg). A conventional pharmacokinetic study was performed simultaneously with the pilot microdialysis study using the same dosing suspension. TAK-285 was detected in the brain even at the last time point when the samples were taken from the animal at the end-point of the microdialysis expt. The apparent absence of TAK-285 in blood and brain dialyzate samples might be explained by a very low recovery of microdialysis probes for TAK-285 and/or by the adsorption of the compd. to the outflow tubing of the microdialysis probes. Results of an in vitro recovery study with TAK-285 were indicative of the strong adsorption of the compd. to the microdialysis tubings. Adding bovine serum albumin (4%, w/v) in perfusion fluids and reducing perfusion flow rate (from 1.0 μL/min to 0.5 μL/min) in in vitro expts. substantially improved the detectability of TAK-285 in dialyzate samples. Application of new perfusion conditions resulted in a manifold increase of the relative recovery of the microdialysis set-up for TAK-285 (from 1.6% to 47%). Subsequent in vivo microdialysis expts. were performed using the modified perfusion conditions in animals dosed with TAK-285 (75 mg/kg, p.o.). Detectable level of unbound TAK-285 was found in the extracellular space in the brain as long as 24-28 h after administration of the drug. The brain-to-blood ratios of the unbound TAK-285 were 0.18 and 0.24 (calcd. from the Cmax values or from the area under the curve [AUC] values) similarly to the brain-to-blood ratios of total TAK-285. On the basis of substantial brain penetration of unbound TAK-285, it is concluded that TAK-285 might have the potential in the treatment of brain metastases of HER2 over-expressing metastatic breast cancer. The methodol. approach described here might help to solve similar problems in detn. of brain penetration of other substances with strong adsorption to the tubing of microdialysis setups.
- 197Nakayama, A.; Takagi, S.; Yusa, T.; Yaguchi, M.; Hayashi, A.; Tamura, T.; Kawakita, Y.; Ishikawa, T.; Ohta, Y. Antitumor activity of TAK-285, an investigational, non-Pgp substrate HER2/EGFR kinase inhibitor, in cultured tumor cells, mouse and rat xenograft tumors, and in an HER2-positive brain metastasis model J. Cancer 2013, 4, 557– 565 DOI: 10.7150/jca.6689[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisVejtr0%253D&md5=d680347de9dd1a09135be86da06307deAntitumor activity of TAK-285, an investigational, non-Pgp substrate HER2/EGFR kinase inhibitor, in cultured tumor cells, mouse and rat xenograft tumors, and in an HER2-positive brain metastasis modelNakayama, Akiko; Takagi, Shinji; Yusa, Tadashi; Yaguchi, Masahiro; Hayashi, Akira; Tamura, Toshiya; Kawakita, Youichi; Ishikawa, Tomoyasu; Ohta, YoshikazuJournal of Cancer (Wyoming, Australia) (2013), 4 (7), 557/1-557/9CODEN: JCWAAL; ISSN:1837-9664. (Ivyspring International Publisher Pty Ltd.)Breast cancer therapy has improved following the development of drugs with specific mol. targets, exemplified by inhibitors of human epidermal growth factor receptor-2 (HER2) or epidermal growth factor receptor (EGFR) such as trastuzumab and lapatinib. However, these drugs have little effect on brain metastasis due to the combined effects of poor penetration of the blood-brain barrier and their removal from the central nervous system (CNS) by the p-glycoprotein (Pgp) drug efflux pump. We investigated the effects of TAK-285, a novel, investigational, dual EGFR/HER2 inhibitor that has been shown to penetrate the CNS and has comparable inhibitory efficacy to lapatinib which is a known Pgp substrate. Tested against a panel of 96 kinases, TAK-285 showed specificity for inhibition of HER family kinases. Unlike lapatinib, TAK-285 is not a substrate for Pgp efflux. In mouse and rat xenograft tumor models, TAK-285 showed antitumor activity against cancers that expressed HER2 or EGFR. TAK-285 was as effective as lapatinib in antitumor activity in a mouse s.c. BT-474 breast cancer xenograft model. TAK-285 was examd. in a model of breast cancer brain metastasis using direct intracranial injection of BT-474-derived luciferase-expressing cells and showed greater inhibition of brain tumor growth compared to animals treated with lapatinib. Our studies suggest that investigational drugs such as TAK-285 that have strong antitumor activity and are not Pgp substrates may be useful in the development of agents with the potential to treat brain metastases.
- 198Kalous, O.; Conklin, D.; Desai, A. J.; O’Brien, N. A.; Ginther, C.; Anderson, L.; Cohen, D. J.; Britten, C. D.; Taylor, I.; Christensen, J. G.; Slamon, D. J.; Finn, R. S. Dacomitinib (PF-00299804), an irreversible Pan-HER inhibitor, inhibits proliferation of HER2-amplified breast cancer cell lines resistant to trastuzumab and lapatinib Mol. Cancer Ther. 2012, 11, 1978– 1987 DOI: 10.1158/1535-7163.MCT-11-0730[Crossref], [PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlWhsrvI&md5=b2b0677cbecb66e1e629742adffb0782Dacomitinib (PF-00299804), an Irreversible Pan-HER Inhibitor, Inhibits Proliferation of HER2-Amplified Breast Cancer Cell Lines Resistant to Trastuzumab and LapatinibKalous, Ondrej; Conklin, Dylan; Desai, Amrita J.; O'Brien, Neil A.; Ginther, Charles; Anderson, Lee; Cohen, David J.; Britten, Carolyn D.; Taylor, Ian; Christensen, James G.; Slamon, Dennis J.; Finn, Richard S.Molecular Cancer Therapeutics (2012), 11 (9), 1978-1987CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)The human EGF (HER) family of receptors has been pursued as therapeutic targets in breast cancer and other malignancies. Trastuzumab and lapatinib are std. treatments for HER2-amplified breast cancer, but a significant no. of patients do not respond or develop resistance to these drugs. Here we evaluate the in vitro activity of dacomitinib (PF-00299804), an irreversible small mol. pan-HER inhibitor, in a large panel of human breast cancer cell lines with variable expression of the HER family receptors and ligands, and with variable sensitivity to trastuzumab and lapatinib. Forty-seven human breast cancer and immortalized breast epithelial lines representing the known mol. subgroups of breast cancer were treated with dacomitinib to det. IC50 values. HER2-amplified lines were far more likely to respond to dacomitinib than nonamplified lines (RR, 3.39; P < 0.0001). Furthermore, HER2 mRNA and protein expression were quant. assocd. with response. Dacomitinib reduced the phosphorylation of HER2, EGFR, HER4, AKT, and ERK in the majority of sensitive lines. Dacomitinib exerted its antiproliferative effect through a combined G0-G1 arrest and an induction of apoptosis. Dacomitinib inhibited growth in several HER2-amplified lines with de novo and acquired resistance to trastuzumab. Dacomitinib maintained a high activity in lines with acquired resistance to lapatinib. This study identifies HER2-amplified breast cancer lines as most sensitive to the antiproliferative effect of dacomitinib and provides a strong rationale for its clin. testing in HER2-amplified breast cancers resistant to trastuzumab and lapatinib. Mol Cancer Ther; 11(9); 1978-87. ©2012 AACR.
- 199Wong, T. W.; Lee, F. Y.; Yu, C.; Luo, F. R.; Oppenheimer, S.; Zhang, H.; Smykla, R. A.; Mastalerz, H.; Fink, B. E.; Hunt, J. T.; Gavai, A. V.; Vite, G. D. Preclinical antitumor activity of BMS-599626, a pan-HER kinase inhibitor that inhibits HER1/HER2 homodimer and heterodimer signaling Clin. Cancer Res. 2006, 12, 6186– 6193 DOI: 10.1158/1078-0432.CCR-06-0642[Crossref], [PubMed], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFWhsbbK&md5=a8350e2eb304a091fa82f1159e44c119Preclinical Antitumor Activity of BMS-599626, a pan-HER Kinase Inhibitor That Inhibits HER1/HER2 Homodimer and Heterodimer SignalingWong, Tai W.; Lee, Francis Y.; Yu, Chiang; Luo, Feng R.; Oppenheimer, Simone; Zhang, Hongjian; Smykla, Richard A.; Mastalerz, Harold; Fink, Brian E.; Hunt, John T.; Gavai, Ashvinikumar V.; Vite, Gregory D.Clinical Cancer Research (2006), 12 (20, Pt. 1), 6186-6193CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: The studies described here are intended to characterize the ability of BMS-599626, a small-mol. inhibitor of the human epidermal growth factor receptor (HER) kinase family, to modulate signaling and growth of tumor cells that depend on HER1 and/or HER2. Exptl. Design: The potency and selectivity of BMS-599626 were assessed in biochem. assays using recombinant protein kinases, as well as in cell proliferation assays using tumor cell lines with varying degrees of dependence on HER1 or HER2 signaling. Modulation of receptor signaling was detd. in cell assays by Western blot analyses of receptor autophosphorylation and downstream signaling. The ability of BMS-599626 to inhibit receptor heterodimer signaling in tumor cells was studied by receptor coimmunopptn. Antitumor activity of BMS-599626 was evaluated using a no. of different xenograft models that represent a spectrum of human tumors with HER1 or HER2 overexpression. Results: BMS-599626 inhibited HER1 and HER2 with IC50 of 20 and 30 nmol/L, resp., and was highly selective when tested against a broad panel of diverse protein kinases. Biochem. studies suggested that BMS-599626 inhibited HER1 and HER2 through distinct mechanisms. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC50 in the range of 0.24 to 1 μmol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling. BMS-599626 had antitumor activity in models that overexpress HER1 (GEO), as well as in models that have HER2 gene amplification (KPL4) or overexpression (Sal2), and there was good correlation between the inhibition of receptor signaling and antitumor activity. Conclusions: BMS-599626 is a highly selective and potent inhibitor of HER1 and HER2 kinases and inhibits tumor cell proliferation through modulation of receptor signaling. BMS-599626 inhibits HER1/HER2 receptor heterodimerization and provides an addnl. mechanism of inhibiting tumors in which receptor coexpression and heterodimerization play a major role in driving tumor growth. The preclin. data support the advancement of BMS-599626 into clin. development for the treatment of cancer.
- 200Desjardins, A.; Reardon, D. A.; Vredenburgh, J. J.; Peters, K.; Trikha, M.; James, J.; Gardner, M.; Brickhouse, A.; Herndon, J. E.; Friedman, H. S. A pharmacokinetic study of AC48 administered twice daily in patients with surgically resectable, recurrent malignant glioma (MG) not on enzyme-inducing antiepileptic drug (EIAED) J. Clin. Oncol. 2011, 29 (Suppl.) 2070
- 201Traxler, P.; Allegrini, P. R.; Brandt, R.; Brueggen, J.; Cozens, R.; Fabbro, D.; Grosios, K.; Lane, H. A.; McSheehy, P.; Mestan, J.; Meyer, T.; Tang, C.; Wartmann, M.; Wood, J.; Caravatti, G. AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity Cancer Res. 2004, 64, 4931– 4941 DOI: 10.1158/0008-5472.CAN-03-3681
- 202Meco, D.; Servidei, T.; Zannoni, G. F.; Martinelli, E.; Prisco, M. G.; de Waure, C.; Riccardi, R. Dual inhibitor AEE788 reduces tumor growth in preclinical models of medulloblastoma Trans. Oncol. 2010, 3, 326– 335 DOI: 10.1593/tlo.10163[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cfmvVWiug%253D%253D&md5=dfd2a6b42009efdd77401ea45f53be7fDual Inhibitor AEE788 Reduces Tumor Growth in Preclinical Models of MedulloblastomaMeco Daniela; Servidei Tiziana; Zannoni Gian Franco; Martinelli Enrica; Prisco Maria Grazia; de Waure Chiara; Riccardi RiccardoTranslational oncology (2010), 3 (5), 326-35 ISSN:.Medulloblastoma is the most frequent malignant pediatric brain tumor with a dismal prognosis in 30% of cases. We examined the activity of AEE788, a dual inhibitor of human epidermal receptor (HER) 1/2 and vascular endothelial growth factor receptor (VEGFR) 1/2, in medulloblastoma preclinical models. Established lines (Daoy and D283), chemoresistant (Daoy(Pt)), and ectopically HER2-overexpressing (Daoy(HER2)) cells expressed diverse levels of total and activated AEE788 target receptors. In vitro, AEE788 inhibited cell proliferation (IC(50) from 1.7 to 3.8 μM) and prevented epidermal growth factor- and neuregulin-induced HER1, HER2, and HER3 activation. Inhibition of Akt paralleled that of HER receptors. In vivo, AEE788 growth inhibited Daoy, Daoy(Pt), and Daoy(HER2) xenografts by 51%, 45%, and 72%, respectively. Immunohistochemical analysis of mock- and HER2-transfected xenografts revealed that the latter showed, along with high HER2 expression, high VEGFR2 staining in tumor and endothelial cells and increased expression of the endothelial marker CD31. AEE788 reduced the activation of target receptors and angiogenesis. In 21 primary medulloblastoma, HER2 expression significantly correlated (P < .01) with VEGFR2 (r = 0.56) and VEGF (r = 0.61). In conclusion, AEE788 shows similar growth-suppressive activities in chemosensitive and chemoresistant medulloblastoma cells in vitro and in vivo. Ectopic HER2 overexpression sensitizes cells to AEE788 in vivo, but not in vitro, possibly through host-mediated processes. Together with the experimental data, the finding that HER2 positively correlates with VEGFR2 and VEGF in human medulloblastoma specimens indicates HER2-overexpressing medulloblastoma as the subset that most likely might benefit from AEE788 treatment.
- 203Goudar, R. K.; Shi, Q.; Hjelmeland, M. D.; Keir, S. T.; McLendon, R. E.; Wikstrand, C. J.; Reese, E. D.; Conrad, C. A.; Traxler, P.; Lane, H. A.; Reardon, D. A.; Cavenee, W. K.; Wang, X. F.; Bigner, D. D.; Friedman, H. S.; Rich, J. N. Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition Mol. Cancer Ther. 2005, 4, 101– 112[PubMed], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXksFyqsA%253D%253D&md5=6b3da386f418d97000bc1a6ac9dff42bCombination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibitionGoudar, Ranjit K.; Shi, Qing; Hjelmeland, Mark D.; Keir, Stephen T.; McLendon, Roger E.; Wikstrand, Carol J.; Reese, Elizabeth D.; Conrad, Charles A.; Traxler, Peter; Lane, Heidi A.; Reardon, David A.; Cavenee, Webster K.; Wang, Xiao-Fan; Bigner, Darell D.; Friedman, Henry S.; Rich, Jeremy N.Molecular Cancer Therapeutics (2005), 4 (1), 101-112CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a single mol. target may slow tumor progression, but tumors are likely not dependent on a signal transduction pathway. Rather, malignant gliomas exhibit sustained mitogenesis and cell growth mediated in part through the effects of receptor tyrosine kinases and the mammalian target of rapamycin (mTOR). AEE788 is a novel orally active tyrosine kinase inhibitor that decreases the kinase activity assocd. with the epidermal growth factor receptor and, at higher concns., the vascular endothelial growth factor receptor 2 (kinase domain region). RAD001 (everolimus) is an orally available mTOR inhibitor structurally related to rapamycin. We hypothesized that combined inhibition of upstream epidermal growth factor receptor and kinase domain region receptors with AEE788 and inhibition of the downstream mTOR pathway with RAD001 would result in increased efficacy against gliomas compared with single-agent therapy. In vitro expts. showed that the combination of AEE788 and RAD001 resulted in increased rates of cell cycle arrest and apoptosis and reduced proliferation more than either agent alone. Combined AEE788 and RAD001 given orally to athymic mice bearing established human malignant glioma tumor xenografts resulted in greater tumor growth inhibition and greater increases in median survival than monotherapy. These studies suggest that simultaneous inhibition of growth factor receptor and mTOR pathways offer increased benefit in glioma therapy.
- 204Reardon, D. A.; Conrad, C. A.; Cloughesy, T.; Prados, M. D.; Friedman, H. S.; Aldape, K. D.; Mischel, P.; Xia, J.; DiLea, C.; Huang, J.; Mietlowski, W.; Dugan, M.; Chen, W.; Yung, W. K. A. Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients Cancer Chemother. Pharmacol. 2012, 69, 1507– 1518 DOI: 10.1007/s00280-012-1854-6[Crossref], [PubMed], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvFOnsbY%253D&md5=cd6133b54e9d7e481af1dc42cd4917d2Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patientsReardon, David A.; Conrad, Charles A.; Cloughesy, Timothy; Prados, Michael D.; Friedman, Henry S.; Aldape, Kenneth D.; Mischel, Paul; Xia, Jane; DiLea, Clifford; Huang, Jerry; Mietlowski, William; Dugan, Margaret; Chen, Wei; Yung, W. K. AlfredCancer Chemotherapy and Pharmacology (2012), 69 (6), 1507-1518CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose Vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) play a significant role in glioblastoma angiogenesis and proliferation, making tyrosine kinase (TK) receptors logical targets for treatment. We evaluated AEE788, a reversible TK inhibitor that inhibits EGFR and VEGFR, in recurrent glioblastoma patients. Methods In this dose-escalation, phase I study, patients with recurrent glioblastoma received AEE788 once daily in 28-day cycles in stratified subgroups: those receiving (1) non-enzyme-inducing anticonvulsants drugs or no anticonvulsants (Group A) and (2) enzyme-inducing anticonvulsant drugs (Group B). A dose-expansion phase stratified patients by surgical eligibility. Primary objectives were to det. dose-limiting toxicity (DLT) and max. tolerated dose; secondary objectives included evaluating (1) safety/tolerability, (2) pharmacokinetics, and (3) preliminary antitumor activity. Results Sixty-four glioblastoma patients were enrolled. Two Group A patients experienced DLTs (proteinuria and stomatitis) at 550 mg; 550 mg was, therefore, the highest dose evaluated and dose limiting. One Group B patient receiving 800 mg experienced a DLT (diarrhea). The initially recommended dose for dose-expansion phase for Group A was 400 mg; addnl. patients received 250 mg to assess the hepatotoxicity. Most frequently reported adverse events (AEs) included diarrhea and rash. Serious AEs, most commonly grade 3/4 liver function test elevations, were responsible for treatment discontinuation in 17% of patients. AEE788 concns. were reduced by EIACD. The best overall response was stable disease (17%). Conclusions Continuous, once-daily AEE788 was assocd. with unacceptable toxicity and minimal activity for the treatment of recurrent glioblastoma. The study was, therefore, discontinued prematurely.
- 205Wissner, A.; Mansour, T. S. The development of HKI-272 and related compounds for the treatment of cancer Arch. Pharm. 2008, 341, 465– 477 DOI: 10.1002/ardp.200800009[Crossref], [PubMed], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVKnsb7E&md5=2e46d99ca74e297e6a7e860634bf096dThe development of HKI-272 and related compounds for the treatment of cancerWissner, Allan; Mansour, Tarek S.Archiv der Pharmazie (Weinheim, Germany) (2008), 341 (8), 465-477CODEN: ARPMAS; ISSN:0365-6233. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The development of HKI-272 and EKB-569 for the treatment of cancer is described. These compds. function as irreversible inhibitors of some members of the ErbB family of receptor tyrosine kinases. In particular, they target epidermal growth factor receptor (EGFR, also known as ErbB-1) and human epidermal growth factor receptor-2 (HER2, also known as ErbB-2). Both, HKI-272 and EKB-569 are 4-anilino-3-cyano quinoline derivs. that contain a 4-(dimethylamino)crotonamide Michael-acceptor group at the 6-position. These compds. inhibit the function of the target enzymes by forming a covalent interaction with a conserved cysteine residue located in the kinase domains of these proteins. The potential advantages of using irreversible inhibitors for this purpose are discussed. We summarize the recent findings concerning some somatic mutations in EGFR and their relevance with respect to the irreversible inhibitors. In particular, we highlight the findings that these irreversible inhibitors retain activity against tumors that have acquired a resistance to the reversible binding inhibitors gefitinib and erlotinib. The promising interim clin. trial results for HKI-272 and EKB-569 in treating colon, lung, and breast cancers are summarized.
- 206Hegedus, C.; Truta-Feles, K.; Antalffy, G.; Varady, G.; Nemet, K.; Ozvegy-Laczka, C.; Keri, G.; Orfi, L.; Szakacs, G.; Settleman, J.; Varadi, A.; Sarkadi, B. Interaction of the EGFR inhibitors gefitinib, vandetanib, pelitinib and neratinib with the ABCG2 multidrug transporter: implications for the emergence and reversal of cancer drug resistance Biochem. Pharmacol. 2012, 84, 260– 267 DOI: 10.1016/j.bcp.2012.04.010
- 207Jani, J. P.; Finn, R. S.; Campbell, M.; Coleman, K. G.; Connell, R. D.; Currier, N.; Emerson, E. O.; Floyd, E.; Harriman, S.; Kath, J. C.; Morris, J.; Moyer, J. D.; Pustilnik, L. R.; Rafidi, K.; Ralston, S.; Rossi, A. M. K.; Steyn, S. J.; Wagner, L.; Winter, S. M.; Bhattacharya, S. K. Discovery and pharmacologic characterization of CP-724,714, a selective ErbB2 tyrosine kinase inhibitor Cancer Res. 2007, 67, 9887– 9893 DOI: 10.1158/0008-5472.CAN-06-3559
- 208Feng, B.; Xu, J. J.; Bi, Y. A.; Mireles, R.; Davidson, R.; Duignan, D. B.; Campbell, S.; Kostrubsky, V. E.; Dunn, M. C.; Smith, A. R.; Wang, H. F. Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724,714 Toxicol. Sci. 2009, 108, 492– 500 DOI: 10.1093/toxsci/kfp033[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktFWjtrk%253D&md5=b5f3892f39f1460d1f33d11e16a683bdRole of Hepatic Transporters in the Disposition and Hepatotoxicity of a HER2 Tyrosine Kinase Inhibitor CP-724,714Feng, Bo; Xu, Jinghai J.; Bi, Yi-An; Mireles, Rouchelle; Davidson, Ralph; Duignan, David B.; Campbell, Scott; Kostrubsky, Vsevolod E.; Dunn, Margaret C.; Smith, Arthur R.; Wang, Huifen F.Toxicological Sciences (2009), 108 (2), 492-500CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)CP-724,714, a potent and selective orally active HER2 tyrosine kinase inhibitor, was discontinued from clin. development due to unexpected hepatotoxicity in cancer patients. Based on the clin. manifestation of the toxicity, CP-724,714 likely exerted its hepatotoxicity via both hepatocellular injury and hepatobiliary cholestatic mechanisms. The direct cytotoxic effect, hepatobiliary disposition of CP-724,714, and its inhibition of active canalicular transport of bile constituents were evaluated in established human hepatocyte models and in vitro transporter systems. CP-724,714 exhibited direct cytotoxicity using human hepatocyte imaging assay technol. with mitochondria identified as a candidate organelle for its off-target toxicity. Addnl., CP-724,714 was rapidly taken up into human hepatocytes, partially via an active transport process, with an uptake clearance approx. fourfold higher than efflux clearance. The major human hepatic uptake transporter, OATP1B1, and efflux transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein, were involved in hepatobiliary clearance of CP-724,714. Furthermore, CP-724,714 displayed a concn.-dependent inhibition of cholyl-lysyl fluorescein and taurocholate (TC) efflux into canaliculi in cryopreserved and fresh cultured human hepatocytes, resp. Likewise, CP-724,714 inhibited TC transport in membrane vesicles expressing human bile salt export pump with an IC50 of 16μM. Finally, CP-724,714 inhibited the major efflux transporter in bile canaliculi, MDR1, with an IC50 of ∼28μM. These results suggest that inhibition of hepatic efflux transporters contributed to hepatic accumulation of drug and bile constituents leading to hepatocellular injury and hepatobiliary cholestasis. This study provides likely explanations for clin. obsd. adverse liver effects of CP-724,714.
- 209Cai, X.; Zhai, H. X.; Wang, J.; Forrester, J.; Qu, H.; Yin, L.; Lai, C. J.; Bao, R.; Qian, C. Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer J. Med. Chem. 2010, 53, 2000– 2009 DOI: 10.1021/jm901453q[ACS Full Text], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhslSgsb0%253D&md5=d4dc339f2fd750d52e511abf3dbf18bdDiscovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a Potent Multi-Acting HDAC, EGFR, and HER2 Inhibitor for the Treatment of CancerCai, Xiong; Zhai, Hai-Xiao; Wang, Jing; Forrester, Jeffrey; Qu, Hui; Yin, Ling; Lai, Cheng-Jung; Bao, Rudi; Qian, ChanggengJournal of Medicinal Chemistry (2010), 53 (5), 2000-2009CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compds. with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clin. development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC50 of 4.4, 2.4, and 15.7 nM, resp. In most tumor cell lines tested, 8 exhibits efficient antiproliferative activity with greater potency than vorinostat (SAHA), erlotinib, lapatinib, and combinations of vorinostat/erlotinib and vorinostat/lapatinib. In vivo, 8 promotes tumor regression or inhibition in various cancer xenograft models including nonsmall cell lung cancer (NSCLC), liver, breast, head and neck, colon, and pancreatic cancers. These results suggest that a single compd. that simultaneously inhibits HDAC, EGFR, and HER2 may offer greater therapeutic benefits in cancer over single-acting agents through the interference with multiple pathways and potential synergy among HDAC and EGFR/HER2 inhibitors.
- 210Barlaam, B.; Anderton, J.; Ballard, P.; Bradbury, R. H.; Hennequin, L. F. A.; Hickinson, D. M.; Kettle, J. G.; Kirk, G.; Klinowska, T.; Lambert-van der Brempt, C.; Trigwell, C.; Vincent, J.; Ogilvie, D. Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors ACS Med. Chem. Lett. 2013, 4, 742– 746 DOI: 10.1021/ml400146c
- 211Xie, H.; Lin, L.; Tong, L.; Jiang, Y.; Zheng, M.; Chen, Z.; Jiang, X.; Zhang, X.; Ren, X.; Qu, W.; Yang, Y.; Wan, H.; Chen, Y.; Zuo, J.; Jiang, H.; Geng, M.; Ding, J. AST1306, a novel irreversible inhibitor of the epidermal growth factor receptor 1 and 2, exhibits antitumor activity both in vitro and in vivo PLoS One 2011, 6, e21487 DOI: 10.1371/journal.pone.0021487
- 212(a) Fife, K. M.; Colman, M. H.; Stevens, G. N.; Firth, I. C.; Moon, D.; Shannon, K. F.; Harman, R.; Petersen-Schaefer, K.; Zacest, A. C.; Besser, M.; Milton, G. W.; McCarthy, W. H.; Thompson, J. F. Determinants of outcome in melanoma patients with cerebral metastases J. Clin. Oncol. 2004, 22, 1293– 1300 DOI: 10.1200/JCO.2004.08.140[Crossref], [PubMed], [CAS], Google Scholar212ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c7lslOktA%253D%253D&md5=1bed3bd78055cfda69f608c3cef92274Determinants of outcome in melanoma patients with cerebral metastasesFife K M; Colman M H; Stevens G N; Firth I C; Moon D; Shannon K F; Harman R; Petersen-Schaefer K; Zacest A C; Besser M; Milton G W; McCarthy W H; Thompson J FJournal of clinical oncology : official journal of the American Society of Clinical Oncology (2004), 22 (7), 1293-300 ISSN:0732-183X.PURPOSE: To analyze prognostic factors, effects of treatment, and survival for patients with cerebral metastases from melanoma. PATIENTS AND METHODS: All melanoma patients with cerebral metastases treated at the Sydney Melanoma Unit between 1952 and 2000 were identified. From 1985 to 2000, patients were diagnosed and treated using consistent modern techniques and this cohort was analyzed in detail. Multivariate analysis of prognostic factors for survival was performed. RESULTS: A total of 1137 patients with cerebral metastases were identified; 686 were treated between 1985 and 2000. For these 686 patients, the median time from primary diagnosis to cerebral metastasis was 3.1 years (range, 0 to 41 years). A total of 646 patients (94%) have died as a result of melanoma. The median survival from the time of diagnosis of cerebral metastasis was 4.1 months (range, 0 to 17.2 years). Treatment was as follows: surgery and postoperative radiotherapy, 158 patients; surgery alone, 47 patients; radiotherapy alone, 236 patients; and supportive care alone, 210 patients. Median survival according to treatment received for these four groups was 8.9, 8.7, 3.4, and 2.1 months, respectively; the differences between surgery and nonsurgery groups were statistically significant. On multivariate analysis, significant factors associated with improved survival were surgical treatment (P <.0001), no concurrent extracerebral metastases (P <.0001), younger age (P =.0007), and longer disease-free interval (P =.036). Prognostic factors analysis confirmed the important influence of patient selection on treatment received. CONCLUSION: This large series documents the characteristics of patients who developed cerebral metastases from melanoma. Median survival was dependent on treatment, which in turn was dependent on patient selection.(b) Sampson, J. H.; Carter, J. H.; Friedman, A. H.; Seigler, H. F. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma J. Neurosurg. 1998, 88, 11– 20 DOI: 10.3171/jns.1998.88.1.0011[Crossref], [PubMed], [CAS], Google Scholar212bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1c%252FotVagtg%253D%253D&md5=19def8072a8f68d34fa042627f3ef7d0Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanomaSampson J H; Carter J H Jr; Friedman A H; Seigler H FJournal of neurosurgery (1998), 88 (1), 11-20 ISSN:0022-3085.UNLABELLED: Brain metastases are a common and devastating complication in patients with malignant melanoma. Therapeutic options for these patients are limited, and the prognosis is usually poor. OBJECT: A retrospective review of 6953 patients with melanoma treated at a single institution was undertaken to identify demographic factors associated with the development of clinically significant brain metastases in 702 of these patients and to determine the factors influencing the prognosis of this population to permit more informed recommendations regarding surgical therapy. METHODS: Factors found to be associated with the development of brain metastases included male gender, primary lesions located on mucosal surfaces or on the skin of the trunk or head and neck, thick or ulcerated primary lesions, and histological findings of acral lentiginous or nodular lesions. The overall median survival time of all patients with brain metastases was 113.2 days, and these metastases contributed to the death of 94.5% of the patients in this group. Patients with primary lesions located in the head or neck region had a significantly shorter survival time relative to other patients with brain metastases, whereas patients with a single brain metastasis, patients without lung or multiple other visceral metastases, and patients whose initial presentation with melanoma included a brain metastasis had a significantly better prognosis. The small group of patients who survived for more than 3 years was characterized by the presence of a surgically treated, single brain metastasis in the absence of other visceral metastatic disease. CONCLUSIONS: Although most patients with brain metastases resulting from melanoma have a dismal prognosis, some who are likely to survive for longer periods can be identified. In these patients surgical resection can significantly prolong meaningful survival. The decision to recommend surgery should be based primarily on the resectability of the brain metastases and on the status and number of other organs with metastatic lesions.
- 213Flaherty, K. T.; Yasothan, U.; Kirkpatrick, P. Vemurafenib Nat. Rev. Drug Discovery 2011, 10, 811– 812 DOI: 10.1038/nrd3579[Crossref], [PubMed], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlyis77I&md5=571edc546d25485f37890e3d62ea90a1VemurafenibFlaherty, Keith. T.; Yasothan, Uma; Kirkpatrick, PeterNature Reviews Drug Discovery (2011), 10 (11), 811-812CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. In August 2011 vemurafenib (Zelboraf; Daiichi Sankyo/Roche), an inhibitor of BRAF kinase, was approved by the US Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation.
- 214Rheault, T. R.; Stellwagen, J. C.; Adjabeng, G. M.; Hornberger, K. R.; Petrov, K. G.; Waterson, A. G.; Dickerson, S. H.; Mook, R. A.; Laquerre, S. G.; King, A. J.; Rossanese, O. W.; Arnone, M. R.; Smitheman, K. N.; Kane-Carson, L. S.; Han, C.; Moorthy, G. S.; Moss, K. G.; Uehling, D. E. Discovery of dabrafenib: a selective inhibitor of Raf kinases with antitumor activity against B-Raf-driven tumors ACS Med. Chem. Lett. 2013, 4, 358– 362 DOI: 10.1021/ml4000063[ACS Full Text], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXit1Sqtr4%253D&md5=4b26187120192c298ca89283e2871fe4Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven TumorsRheault, Tara R.; Stellwagen, John C.; Adjabeng, George M.; Hornberger, Keith R.; Petrov, Kimberly G.; Waterson, Alex G.; Dickerson, Scott H.; Mook, Robert A.; Laquerre, Sylvie G.; King, Alastair J.; Rossanese, Olivia W.; Arnone, Marc R.; Smitheman, Kimberly N.; Kane-Carson, Laurie S.; Han, Chao; Moorthy, Ganesh S.; Moss, Katherine G.; Uehling, David E.ACS Medicinal Chemistry Letters (2013), 4 (3), 358-362CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-RafV600E mutated enzyme has been obsd. in a no. of human tumors, including melanomas. Herein, we report the discovery and biol. evaluation of GSK2118436 (dabrafenib, I), a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-RafV600E human melanoma. GSK2118436 was identified as a development candidate, and early clin. results have shown significant activity in patients with B-Raf mutant melanoma.
- 215Hoeflich, K. P.; Merchant, M.; Orr, C.; Chan, J.; Den Otter, D.; Berry, L.; Kasman, I.; Koeppen, H.; Rice, K.; Yang, N. Y.; Engst, S.; Johnston, S.; Friedman, L. S.; Belvin, M. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition Cancer Res. 2012, 72, 210– 219 DOI: 10.1158/0008-5472.CAN-11-1515[Crossref], [PubMed], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVCltA%253D%253D&md5=40032bf35d5e6335856a645d5c331df8Intermittent Administration of MEK Inhibitor GDC-0973 plus PI3K Inhibitor GDC-0941 Triggers Robust Apoptosis and Tumor Growth InhibitionHoeflich, Klaus P.; Merchant, Mark; Orr, Christine; Chan, Jocelyn; Den Otter, Doug; Berry, Leanne; Kasman, Ian; Koeppen, Hartmut; Rice, Ken; Yang, Nai-Ying; Engst, Stefan; Johnston, Stuart; Friedman, Lori S.; Belvin, MarciaCancer Research (2012), 72 (1), 210-219CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Combinations of MAP/ERK kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors have shown promise in preclin. cancer models, leading to the initiation of clin. trials cotargeting these two key cancer signaling pathways. GDC-0973, a novel selective MEK inhibitor, and GDC-0941, a class I PI3K inhibitor, are in early stage clin. trials as both single agents and in combination. The discovery of these selective inhibitors has allowed investigation into the precise effects of combining inhibitors of two major signaling branches downstream of RAS. Here, we investigated multiple biomarkers in the mitogen-activated protein kinase (MAPK) and PI3K pathway to search for points of convergence that explain the increased apoptosis seen in combination. Using washout studies in vitro and alternate dosing schedules in mice, we showed that intermittent inhibition of the PI3K and MAPK pathway is sufficient for efficacy in BRAF and KRAS mutant cancer cells. The combination of GDC-0973 with the PI3K inhibitor GDC-0941 resulted in combination efficacy in vitro and in vivo via induction of biomarkers assocd. with apoptosis, including Bcl-2 family proapoptotic regulators. Therefore, these data suggest that continuous exposure of MEK and PI3K inhibitors in combination is not required for efficacy in preclin. cancer models and that sustained effects on downstream apoptosis biomarkers can be obsd. in response to intermittent dosing. Cancer Res; 72(1); 210-9.
- 216Abe, H.; Kikuchi, S.; Hayakawa, K.; Iida, T.; Nagahashi, N.; Maeda, K.; Sakamoto, J.; Matsumoto, N.; Miura, T.; Matsumura, K.; Seki, N.; Inaba, T.; Kawasaki, H.; Yamaguchi, T.; Kakefuda, R.; Nanayama, T.; Kurachi, H.; Hori, Y.; Yoshida, T.; Kakegawa, J.; Watanabe, Y.; Gilmartin, A. G.; Richter, M. C.; Moss, K. G.; Laquerre, S. G. Discovery of a highly potent and selective MEK inhibitor: GSK1120212 (JTP-74057 DMSO solvate) ACS Med. Chem. Lett. 2011, 2, 320– 324 DOI: 10.1021/ml200004g[ACS Full Text], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisFeksb0%253D&md5=0cb3bfa4e142b8d5ecc591e6792cd692Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate)Abe, Hiroyuki; Kikuchi, Shinichi; Hayakawa, Kazuhide; Iida, Tetsuya; Nagahashi, Noboru; Maeda, Katsuya; Sakamoto, Johei; Matsumoto, Noriaki; Miura, Tomoya; Matsumura, Koji; Seki, Noriyoshi; Inaba, Takashi; Kawasaki, Hisashi; Yamaguchi, Takayuki; Kakefuda, Reina; Nanayama, Toyomichi; Kurachi, Hironori; Hori, Yoshikazu; Yoshida, Takayuki; Kakegawa, Junya; Watanabe, Yoshihiro; Gilmartin, Aidan G.; Richter, Mark C.; Moss, Katherine G.; Laquerre, Sylvie G.ACS Medicinal Chemistry Letters (2011), 2 (4), 320-324CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) represents a promising strategy for the discovery of a new generation of anticancer chemotherapeutics. Our synthetic efforts, beginning from the lead compd. 2, were directed at improving antiproliferative activity against cancer cells as well as various drug properties. These efforts led to the discovery of N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethylsulfoxide solvate (GSK1120212, JTP-74057 DMSO solvate; 1), a selective and highly potent MEK inhibitor with improved drug properties. We further confirmed that the antiproliferative activity correlates with cellular MEK inhibition and obsd. significant antitumor activity with daily oral dosing of 1 in a tumor xenograft model. These qualities led to the selection of 1 for clin. development.
- 217Myung, J. K.; Cho, H.; Park, C.-K.; Kim, S. K.; Lee, S. H.; Park, S. H. Analysis of the BRAF V600E mutation in central nervous system tumors Transl. Oncol. 2012, 5, 430– 436 DOI: 10.1593/tlo.12328[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s3pvVKmtw%253D%253D&md5=5b658d1f30e6051ee480912ea87c77b8Analysis of the BRAF(V600E) Mutation in Central Nervous System TumorsMyung Jae Kyung; Cho Hwajin; Park Chul-Kee; Kim Seung-Ki; Lee Se-Hoon; Park Sung-HyeTranslational oncology (2012), 5 (6), 430-6 ISSN:.BRAF(V600E) mutations are involved in the development of melanoma, colon cancer, and papillary thyroid carcinoma. These mutations are also found in primary brain tumors at low to moderate frequencies. In this study, we investigated a series of brain tumors to determine the prevalence and associated clinicopathologic features of BRAF(V600E) mutations. By direct sequencing, we analyzed 223 brain tumors, including 51 gangliogliomas (GGs), 45 pilocytic astrocytomas (PAs), 12 pleomorphic xanthoastrocytomas (PXAs), 35 glioblastomas (GBs), 28 anaplastic astrocytomas (AAs), 44 oligodendroglial tumors (ODGs), 3 anaplastic oligoastrocytomas, and 5 diffuse astrocytomas. Thirty-six cases (16.1%) exhibited the BRAF(V600E) mutation, including 66.7% of PXAs, 23.5% of GGs, 15.6% of PAs, and 9.7% of the malignant gliomas; the latter included 14.3% of AAs, 8.6% of GBs, and 4.5% of ODGs. Copy number aberration at the 7q34 (BRAF) locus was found in 73.1% of PAs and 50% of PXAs. 9p Homozygous deletion was found in 66.7% of PXAs, but it was not correlated with the BRAF(V600E) mutation. Patients' age, sex, histologic grade, and progression-free survival were also not correlated with the BRAF(V600E) mutation. The BRAF(V600E) mutation in brain tumors did not have prognostic value but is certainly a diagnostic marker and therapeutic target, not only for pediatric low-grade gliomas but also for malignant gliomas, even though the rate of mutation was not high. These results should be verified in a larger study with more cases and a longer follow-up period to overcome the limitation of small sample size.
- 218Kieran, M. W. Targeting BRAF in pediatric brain tumors. In American Society of Clinical Oncology 2014 Educational Book; Dizon, D. S.; Pennell, N.; Burke, L.; Carter, D.; Dottellis, D., Eds.; American Society of Clinical Oncology: Alexandria, VA, 2014; pp e436– e440, DOI: DOI: 10.14694/EdBook_AM.2014.34.e436 .
- 219See, W. L.; Tan, I. L.; Mukherjee, J.; Nicolaides, T.; Pieper, R. O. Sensitivity of glioblastomas to clinically available MEK inhibitors is defined by neurofibromin 1 deficiency Cancer Res. 2012, 72, 3350– 3359 DOI: 10.1158/0008-5472.CAN-12-0334
- 220(a) McCubrey, J. A.; Steelman, L. S.; Chappell, W. H.; Abrams, S. L.; Franklin, R. A.; Montalto, G.; Cervello, M.; Libra, M.; Candido, S.; Malaponte, G.; Mazzarino, M. C.; Fagone, P.; Nicoletti, F.; Basecke, J.; Mijatovic, S.; Maksimovic-Ivanic, D.; Milella, M.; Tafuri, A.; Chiarini, F.; Evangelisti, C.; Cocco, L.; Martelli, A. M. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance Oncotarget 2012, 3, 1068– 1111 DOI: 10.18632/oncotarget.659(b) Huang, T.; Karsy, M.; Zhuge, J.; Zhong, M.; Liu, D. B-Raf and the inhibitors: from bench to bedside J. Hematol. Oncol. 2013, 6, 30 DOI: 10.1186/1756-8722-6-30[Crossref], [PubMed], [CAS], Google Scholar220bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXotFWrsLw%253D&md5=62c83f28798a093cf4be76376020721bB-Raf and the inhibitors: from bench to bedsideHuang, Tiangui; Karsy, Michael; Zhuge, Jian; Zhong, Minghao; Liu, DelongJournal of Hematology & Oncology (2013), 6 (), 30CODEN: JHOOAO; ISSN:1756-8722. (BioMed Central Ltd.)A review. The B-Raf protein is a key signaling mol. in the mitogen activated protein kinase (MAPK) signaling pathway and has been implicated in the pathogenesis of a variety of cancers. An important V600E mutation has been identified and can cause constitutive B-Raf activation. Recent studies have evaluated a variety of small mol. inhibitors targeting B-Raf, including PLX4032/vemurafenib, dabrafenib, LGX818, GDC0879, XL281, ARQ736, PLX3603 (RO5212054), and RAF265. Therapeutic resistance has been identified and various mechanisms described. This review also discussed the current understanding of B-Raf signaling mechanism, methods of mutation detection, treatment strategies as well as potential methods of overcoming therapeutic resistance.
- 221(a) Zhao, Y.; Adjei, A. A. The clinical development of MEK inhibitors Nat. Rev. Clin. Oncol. 2014, 11, 385– 400 DOI: 10.1038/nrclinonc.2014.83[Crossref], [PubMed], [CAS], Google Scholar221ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXosVyqtbo%253D&md5=c81e0a5f52a8d4d482b7d617901d67ebThe clinical development of MEK inhibitorsZhao, Yujie; Adjei, Alex A.Nature Reviews Clinical Oncology (2014), 11 (7), 385-400CODEN: NRCOAA; ISSN:1759-4774. (Nature Publishing Group)A review. Aberrant activation of the RAS-RAF-MEK-ERK1/2 pathway occurs in more than 30% of human cancers. As part of this pathway, MEK1 and MEK2 have crucial roles in tumorigenesis, cell proliferation and inhibition of apoptosis and, therefore, MEK1/2 inhibition is an attractive therapeutic strategy in a no. of cancers. Highly selective and potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed and assessed in numerous clin. studies over the past decade. These agents are not efficacious in a broad range of unselected cancers, although single-agent antitumor activity has been detected mainly in tumors that harbor mutations in genes encoding the members of the RAS and RAF protein families, such as certain melanomas. Combinations of MEK1/2 inhibitors and cytotoxic chemotherapy, and/or other targeted agents are being studied to expand the efficacy of this class of agents. Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for the future clin. development of MEK inhibitors. We discuss the clin. experience with MEK inhibitors to date, and consider the novel approaches to MEK-inhibitor therapy that might improve outcomes and lead to the wider use of such treatments.(b) Akinleye, A.; Furqan, M.; Mukhi, N.; Ravella, P.; Liu, D. MEK and the inhibitors: from bench to bedside J. Hematol. Oncol. 2013, 6, 27 DOI: 10.1186/1756-8722-6-27[Crossref], [PubMed], [CAS], Google Scholar221bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmvFejurg%253D&md5=8443b97a166e26e53bd0b81641ed2114MEK and the inhibitors: from bench to bedsideAkinleye, Akintunde; Furqan, Muhammad; Mukhi, Nikhil; Ravella, Pavan; Liu, DelongJournal of Hematology & Oncology (2013), 6 (), 27CODEN: JHOOAO; ISSN:1756-8722. (BioMed Central Ltd.)A review. Four distinct MAP kinase signaling pathways involving 7 MEK enzymes have been identified. MEK1 and MEK2 are the prototype members of MEK family proteins. Several MEK inhibitors are in clin. trials. Trametinib is being evaluated by FDA for the treatment of metastatic melanoma with BRAF V600 mutation. Selumetinib has been studied in combination with docetaxel in phase II randomized trial in previously treated patients with advanced lung cancer. Selumetinib group had better response rate and progression-free survival. This review also summarized new MEK inhibitors in clin. development, including pimasertib, refametinib, PD-0325901, TAK733, MEK162 (ARRY 438162), RO5126766, WX-554, RO4987655 (CH4987655), GDC-0973 (XL518) and AZD8330.(c) McDermott, L.; Qin, C. Allosteric MEK1/2 Inhibitors for the Treatment of Cancer: An Overview. J. Drug Res. Dev. 2015, 1, DOI: DOI: 10.16966/2470-1009.101 ; http://dx.doi.org/10.16966/2470-1009.101.
- 222(a) Rochet, N. M.; Dronca, R. S.; Kottschade, L. A.; Chavan, R. N.; Gorman, B.; Gilbertson, J. R.; Markovic, S. N. Melanoma brain metastases and vemurafenib: need for further investigation Mayo Clin. Proc. 2012, 87, 976– 981 DOI: 10.1016/j.mayocp.2012.07.006[Crossref], [PubMed], [CAS], Google Scholar222ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntlaqsQ%253D%253D&md5=7d8eb3392d87022d61d94698445591c2Melanoma brain metastases and vemurafenib: need for further investigationRochet, Nicole M.; Dronca, Roxana S.; Kottschade, Lisa A.; Chavan, Rahul N.; Gorman, Brian; Gilbertson, Julie R.; Markovic, Svetomir N.Mayo Clinic Proceedings (2012), 87 (10), 976-981CODEN: MACPAJ; ISSN:0025-6196. (Elsevier)Brain metastases are a major cause of morbidity and mortality in patients with advanced melanoma. With the development of targeted agents for the treatment of metastatic melanoma, a great deal of interest has focused on whether selective BRAF inhibitors may play a role in the treatment of brain metastases in lieu of or in addn. to surgery and/or radiation therapy. However, relatively little is known about the intracranial effectiveness of vemurafenib, the only US Food and Drug Administration-approved selective BRAF V600E inhibitor, because patients with brain metastases have historically been excluded from vemurafenib clin. trials. We describe 3 patients with BRAF V600E mutation metastatic melanoma in whom treatment with vemurafenib resulted in prompt extracranial disease response but progression of metastatic disease in the brain. Further, we discuss possible mechanisms responsible for the suboptimal central nervous system response obsd. in these patients and alternative therapies for patients with melanoma metastatic to the brain.(b) Gummadi, T.; Zhang, B. Y.; Valpione, S.; Kim, C.; Kottschade, L. A.; Mittapalli, R. K.; Chiarion-Sileni, V.; Pigozzo, J.; Elmquist, W. F.; Dudek, A. Impact of BRAF mutation and BRAF inhibition on melanoma brain metastases Melanoma Res. 2015, 25, 75– 79 DOI: 10.1097/CMR.0000000000000133[Crossref], [PubMed], [CAS], Google Scholar222bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFKqsbjK&md5=3570e6ac8c3f9b28c6ffb5766ea68fe0Impact of BRAF mutation and BRAF inhibition on melanoma brain metastasesGummadi, Tulasi; Zhang, Ben Y.; Valpione, Sara; Kim, Chul; Kottschade, Lisa A.; Mittapalli, Rajendar K.; Chiarion-Sileni, Vanna; Pigozzo, Jacopo; Elmquist, William F.; Dudek, Arkadiusz Z.Melanoma Research (2015), 25 (1), 75-79CODEN: MREEEH; ISSN:0960-8931. (Lippincott Williams & Wilkins)The impact of BRAF mutations in metastatic melanoma on the incidence of brain metastases and melanoma prognosis and the effect of BRAF inhibitors on the incidence of brain metastases has not been defined. Therefore, a retrospective anal. of patients with metastatic melanoma treated at three institutions was carried out to examine the impact of BRAF mutations and a BRAF inhibitor, vemurafenib, on the incidence of brain metastases. A retrospective review of 436 records revealed no difference in the incidence of brain metastases between patients with BRAF-mutated tumors vs. those without (incidence rate ratio=1.11, 95% confidence interval: 0.80-1.53; P=0.53). A lower incidence of brain metastases was obsd. in patients with BRAF-mutated tumors who took vemurafenib before the development of brain metastases vs. those who did not (incidence rate ratio=0.51, 95% confidence interval: 0.30-0.86; P=0.009). Although treatment with vemurafenib led to improvement in extracranial disease control, it did not significantly affect progression of existing intracranial disease and survival in these patients (P=0.7). Although our previous preclin. data have indicated that penetration of vemurafenib into the brain is limited, our retrospective anal. showed that there was a lower incidence of brain metastases in patients with BRAF-mutated tumors who took vemurafenib before the diagnosis of brain metastases.(c) Dummer, R.; Goldinger, S. M.; Turtschi, C. P.; Eggmann, N. B.; Michielin, O.; Mitchell, L.; Veronese, L.; Hilfikeer, P. R.; Felderer, L.; Rinderknecht, J. D. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study Eur. J. Cancer 2014, 50, 611– 621 DOI: 10.1016/j.ejca.2013.11.002(d) Robinson, G. W.; Orr, B. A.; Gajjar, A. Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multi-forme after BRAF Inhibitor therapy BMC Cancer 2014, 14, 258 DOI: 10.1186/1471-2407-14-258
- 223(a) Falchook, G. S.; Long, G. V.; Kurzrock, R.; Kim, K. B.; Arkenau, T. H.; Brown, M. P.; Hamid, O.; Infante, J. R.; Millward, M.; Pavlick, A. C.; O’Day, S. J.; Blackman, S. C.; Curtis, C. M.; Lebowitz, P.; Ma, B.; Ouellet, D.; Kefford, R. F. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase I dose-escalation trial Lancet 2012, 379, 1893– 1901 DOI: 10.1016/S0140-6736(12)60398-5(b) Long, G. V.; Trefzer, U.; Davies, M. A.; Kefford, R. F.; Ascierto, P. A.; Chapman, P. B.; Puzanov, I.; Hauschild, A.; Robert, C.; Algazi, A.; Mortier, L.; Tawbi, H.; Wilhelm, T.; Zimmer, L.; Switzky, J.; Swann, S.; Martin, A. M.; Guckert, M.; Goodman, V.; Streit, M.; Kirkwood, J. M.; Schadendorf, D. Dabrafenib in patients with Val600Glu or V600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicenter, open-label, phase 2 trial Lancet Oncol. 2012, 13, 1087– 1095 DOI: 10.1016/S1470-2045(12)70431-X[Crossref], [PubMed], [CAS], Google Scholar223bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1WqurzP&md5=dacdaec26bdcb06f1ed07b682c812785Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trialLong, Georgina V.; Trefzer, Uwe; Davies, Michael A.; Kefford, Richard F.; Ascierto, Paolo A.; Chapman, Paul B.; Puzanov, Igor; Hauschild, Axel; Robert, Caroline; Algazi, Alain; Mortier, Laurent; Tawbi, Hussein; Wilhelm, Tabea; Zimmer, Lisa; Switzky, Julie; Swann, Suzanne; Martin, Anne-Marie; Guckert, Mary; Goodman, Vicki; Streit, Michael; Kirkwood, John M.; Schadendorf, DirkLancet Oncology (2012), 13 (11), 1087-1095CODEN: LOANBN; ISSN:1470-2045. (Elsevier Ltd.)Background: Brain metastases are common in patients with metastatic melanoma and median overall survival from their diagnosis is typically 17-22 wk. We assessed dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain. Methods: We undertook a multicentre, open-label, phase 2 trial in 24 centers in six countries. We enrolled patients with histol. confirmed Val600Glu or Val600Lys BRAF-mutant melanoma and at least one asymptomatic brain metastasis (≥5 mm and ≤40 mm in diam.). Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncol. Group performance status of 0 or 1, and had adequate organ function. Patients were split into two cohorts: those in cohort A had not received previous local treatment for brain metastases and those in cohort B had progressive brain metastases after previous local treatments. Patients received 150 mg oral dabrafenib twice a day until disease progression, death, or unacceptable adverse events. The primary endpoint was the proportion of patients with Val600Glu BRAF-mutant melanoma who achieved an overall intracranial response, which was defined as a complete response or partial response assessed with a modified form of Response Evaluation Criteria in Solid Tumors (RECIST 1.1). We included patients who received at least one dose of dabrafenib in efficacy and safety analyses. This study is registered with ClinicalTrials.gov, no. NCT01266967. Findings: Between Feb 2, 2011, and Aug 5, 2011, we enrolled 172 patients: 89 (52%) in cohort A and 83 (48%) in cohort B. 139 (81%) had Val600Glu BRAF-mutant melanoma. 29 (39·2%, 95% CI 28·0-51·2) of 74 patients with Val600Glu BRAF-mutant melanoma in cohort A achieved an overall intracranial response, as did 20 (30·8%, 19·9-43·4) of 65 in cohort B. One (6·7%, 0·2-31·9) of 15 patients with Val600Lys BRAF-mutant melanoma achieved an overall intracranial response in cohort A, as did four (22·2%, 6·4-47·6) of 18 such patients in cohort B. Treatment-related adverse events of grade 3 or worse occurred in 38 (22%) patients. Eleven (6%) patients developed squamous-cell carcinoma (five [6%] patients in cohort A, of whom one also had keratoacanthoma; six [7%] in cohort B). Four grade 4 treatment-related adverse events occurred in cohort A: one blood amylase increase, one convulsion, one lipase increase, and one neutropenia. Two grade 4 events occurred in cohort B: one agranulocytosis and one intracranial hemorrhage. 51 (30%) patients had a serious adverse event. The three most frequent serious adverse events were pyrexia (ten [6%] patients), intracranial hemorrhage (ten [6%]; one treatment-related), and squamous-cell carcinoma (11 [6%]). Interpretation: Dabrafenib has activity and an acceptable safety profile in patients with Val600Glu BRAF-mutant melanoma and brain metastases irresp. of whether they are untreated or have been previously treated but have progressed. Funding: GlaxoSmithKline.
- 224Vaidhyanathan, S.; Mittapalli, R. K.; Sarkaria, J. N.; Elmquist, W. F. Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases Drug Metab. Dispos. 2014, 42, 1292– 1300 DOI: 10.1124/dmd.114.058339
- 225(a) Mittapalli, R. K.; Vaidhyanathan, S.; Sane, R.; Elmquist, W. F. Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032) J. Pharmacol. Exp. Ther. 2012, 342, 33– 40 DOI: 10.1124/jpet.112.192195[Crossref], [PubMed], [CAS], Google Scholar225ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVOktbjE&md5=68483daffd06025efca561991a4ae0f1Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032)Mittapalli, Rajendar K.; Vaidhyanathan, Shruthi; Sane, Ramola; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2012), 342 (1), 33-40CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Vemurafenib [N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide(PLX4032)] is a novel small-mol. BRAF inhibitor, recently approved by the Food and Drug Administration for the treatment of patients with metastatic melanoma with a BRAFV600E mutation. The objective of this study was to investigate the role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in the distribution of vemurafenib to the central nervous system. In vitro studies conducted in transfected Madin-Darby canine kidney II cells show that the intracellular accumulation of vemurafenib is significantly restricted because of active efflux by P-gp and BCRP. Bidirectional flux studies indicated greater transport in the basolateral-to-apical direction than the apical-to-basolateral direction because of active efflux by P-gp and BCRP. The selective P-gp and BCRP inhibitors zosuquidar and (3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino(1',2':1,6)pyrido(3,4-b)indole-3-propanoic acid-1,1-dimethylethyl ester (Ko143) were able to restore the intracellular accumulation and bidirectional net flux of vemurafenib. The in vivo studies revealed that the brain distribution coeff. (area under the concn. time profile of brain/area under the concn. time profile of plasma) of vemurafenib was 0.004 in wild-type mice. The steady-state brain-to-plasma ratio of vemurafenib was 0.035 ± 0.009 in Mdr1a/b(-/-) mice, 0.009 ± 0.006 in Bcrp1(-/-) mice, and 1.00 ± 0.19 in Mdr1a/b(-/-)Bcrp1(-/-) mice compared with 0.012 ± 0.004 in wild-type mice. These data indicate that the brain distribution of vemurafenib is severely restricted at the blood-brain barrier because of active efflux by both P-gp and BCRP. This finding has important clin. significance given the ongoing trials examg. the efficacy of vemurafenib in brain metastases of melanoma.(b) Mittapalli, R. K.; Vaidhyanathan, S.; Dudek, A. Z.; Elmquist, W. F. Mechanisms limiting distribution of the threonine-protein kinase B-RafV600E inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases J. Pharmacol. Exp. Ther. 2013, 344, 655– 664 DOI: 10.1124/jpet.112.201475[Crossref], [PubMed], [CAS], Google Scholar225bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjvVaju7Y%253D&md5=a1017480b1ec89e0942480fe60c7f4a8Mechanisms limiting distribution of the threonine-protein kinase B-RaFV600E inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastasesMittapalli, Rajendar K.; Vaidhyanathan, Shruthi; Dudek, Arkadiusz Z.; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2013), 344 (3), 655-664CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Brain metastases are a common cause of death in stage IV metastatic melanoma. Dabrafenib is a BRAF (gene encoding serine/threonine-protein kinase B-Raf) inhibitor that has been developed to selectively target the valine 600 to glutamic acid substitution (BRAFV600E), which is commonly found in metastatic melanoma. Clin. trials with dabrafenib have shown encouraging results; however, the central nervous system distribution of dabrafenib remains unknown. Thus, the objective of the current study was to evaluate the brain distribution of dabrafenib in mice, and to see whether active efflux by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restricts its delivery across the blood-brain barrier (BBB). In vitro accumulation studies conducted in Madin-Darby canine kidney II cells indicate that dabrafenib is an avid substrate for both P-gp and BCRP. Directional flux studies revealed greater transport in the basolateral to apical direction with cor. efflux ratios greater than 2 for both P-gp and Bcrp1 transfected cell lines. In vivo, the ratio of area under the concn.-time curve (AUC)brain to AUCplasma (Kp) of dabrafenib after an i.v. dose (2.5 mg/kg) was 0.023, which increased by 18-fold in Mdr1 a/b-/-Bcrp1-/- mice to 0.42. Dabrafenib plasma exposure was ∼2-fold greater in Mdr1 a/b-/-Bcrp1-/- mice as compared with wild-type with an oral dose (25 mg/kg); however, the brain distribution was increased by ∼10-fold with a resulting Kp of 0.25. Further, compared with vemurafenib, another BRAFV600E inhibitor, dabrafenib showed greater brain penetration with a similar dose. In conclusion, the dabrafenib brain distribution is limited in an intact BBB model, and the data presented herein may have clin. implications in the prevention and treatment of melanoma brain metastases.
- 226Williams, T. E.; Subramanian, S.; Verhagen, J.; McBride, C. M.; Costales, A.; Sung, L.; Antonios-McCrea, W.; McKenna, M.; Louie, A. K.; Ramurthy, S.; Levine, B.; Shafer, C. M.; Machajewski, T.; Renhowe, P. A.; Appleton, B. A.; Amiri, P.; Chou, J.; Stuart, D.; Aardalen, K.; Poon, D. Discovery of RAF265: a potent mut-B-Raf inhibitor for the treatment of metastatic melanoma ACS Med. Chem. Lett. 2015, 6, 961– 965 DOI: 10.1021/ml500526p[ACS Full Text], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Kms7jO&md5=d8292ddc806a7a1b352f34abc232d84dDiscovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic MelanomaWilliams, Teresa E.; Subramanian, Sharadha; Verhagen, Joelle; McBride, Christopher M.; Costales, Abran; Sung, Leonard; Antonios-McCrea, William; McKenna, Maureen; Louie, Alicia K.; Ramurthy, Savithri; Levine, Barry; Shafer, Cynthia M.; Machajewski, Timothy; Renhowe, Paul A.; Appleton, Brent A.; Amiri, Payman; Chou, James; Stuart, Darrin; Aardalen, Kimberly; Poon, DanielACS Medicinal Chemistry Letters (2015), 6 (9), 961-965CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clin. trials.
- 227Liu, X.; Ide, J. L.; Norton, I.; Marchionni, M. A.; Ebling, M. C.; Wang, L. Y.; Davis, E.; Sauvageot, C. M.; Kesari, S.; Kellersberger, K. A.; Easterling, M. L.; Santagata, S.; Stuart, D. D.; Alberta, J.; Agar, J. N.; Stiles, C. D.; Agar, N. Y. R. Molecular imaging of drug transit through the blood-brain barrier with MALDI mass spectrometry imaging Sci. Rep. 2013, 3, 2859 DOI: 10.1038/srep02859[Crossref], [PubMed], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c%252FlvFCiug%253D%253D&md5=a496de9b3b29c80f27b8174d9da8e715Molecular imaging of drug transit through the blood-brain barrier with MALDI mass spectrometry imagingLiu Xiaohui; Ide Jennifer L; Norton Isaiah; Marchionni Mark A; Ebling Maritza C; Wang Lan Y; Davis Erin; Sauvageot Claire M; Kesari Santosh; Kellersberger Katherine A; Easterling Michael L; Santagata Sandro; Stuart Darrin D; Alberta John; Agar Jeffrey N; Stiles Charles D; Agar Nathalie Y RScientific reports (2013), 3 (), 2859 ISSN:.Drug transit through the blood-brain barrier (BBB) is essential for therapeutic responses in malignant glioma. Conventional methods for assessment of BBB penetrance require synthesis of isotopically labeled drug derivatives. Here, we report a new methodology using matrix assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) to visualize drug penetration in brain tissue without molecular labeling. In studies summarized here, we first validate heme as a simple and robust MALDI MSI marker for the lumen of blood vessels in the brain. We go on to provide three examples of how MALDI MSI can provide chemical and biological insights into BBB penetrance and metabolism of small molecule signal transduction inhibitors in the brain - insights that would be difficult or impossible to extract by use of radiolabeled compounds.
- 228Liveblogging First-Time Disclosures of Drug Structures from #ACSNOLA. http://cenblog.org/the-haystack/2013/04/liveblogging-first-time-disclosures-of-drug-structures-from-acsnola/ (ccessed June 10, 2016) .
- 229Rusconi, P.; Caiola, E.; Broggini, M. Ras/Raf/MEK inhibitors in oncology Curr. Med. Chem. 2012, 19, 1164– 1176 DOI: 10.2174/092986712799320510[Crossref], [PubMed], [CAS], Google Scholar229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1Kktro%253D&md5=8f035e72d81b5703de0e5782102726e9RAS/RAF/MEK inhibitors in oncologyRusconi, P.; Caiola, E.; Broggini, M.Current Medicinal Chemistry (2012), 19 (8), 1164-1176CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. The RAS/RAF/MEK signaling pathway plays a central role in mediating both proliferation and survival of cancer cells. These proteins are a group of serine/threonine kinases activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface towards both nuclear and cytosolic targets. In combination with several other signaling pathways, they can differentially alter phosphorylation status of the transcription factors. A controlled regulation of these cascades is involved in cell proliferation and differentiation, whereas an unregulated activation of these kinases can result in oncogenesis. Dysregulation of the RAS/RAF/MEK pathway was detected in > 30% of human tumors, however mutations in the MEK1 and MEK2 genes are seldom, so that hyperactivation of MEK1/2 usually results from gain-of-function mutations in RAS and/or B-RAF. In addn., alteration of the pathways is often assocd. with drug resistance in the clinic, such as the case of K-RAS mutant expressing tumors. Since RAS protein is a difficult target, alternative ways altering post-translational modifications using farnesyl transferase inhibitors were adopted. Drug discovery programs have therefore largely focused on B-RAF and MEK. In this review we will discuss the most promising strategies developed to target these kinases and the most recent inhibitors facing the preclin. and clin. setting, also considering their structure-activity relationship (SAR).
- 230Choo, E. F.; Ly, J.; Chan, J.; Shahidi-Latham, S. K.; Messick, K.; Plise, E.; Quiason, C. M.; Yang, L. Role of P-glycoprotein on the brain penetration and brain pharmacodynamic activity of the MEK inhibitor cobimetinib Mol. Pharmaceutics 2014, 11, 4199– 4207 DOI: 10.1021/mp500435s[ACS Full Text], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFygtLbO&md5=90fef69297bcd8db6878894b65949b13Role of P-Glycoprotein on the Brain Penetration and Brain Pharmacodynamic Activity of the MEK Inhibitor CobimetinibChoo, Edna F.; Ly, Justin; Chan, Jocelyn; Shahidi-Latham, Sheerin K.; Messick, Kirsten; Plise, Emile; Quiason, Cristine M.; Yang, LuluMolecular Pharmaceutics (2014), 11 (11), 4199-4207CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Cobimetinib is a MEK inhibitor currently in clin. trials as an anticancer agent. The objectives of this study were to det. in vitro and in vivo if cobimetinib is a substrate of P-glycoprotein (P-gp) and/or breast cancer resistance protein (Bcrp1) and to assess the implications of efflux on cobimetinib pharmacokinetics (PK), brain penetration, and target modulation. Cell lines transfected with P-gp or Bcrp1 established that cobimetinib was a substrate of P-gp but not a substrate of Bcrp1. In vivo, after i.v. and oral administration of cobimetinib to FVB (wild-type; WT), Mdr1a/b(-/-), Bcrp1 (-/-), and Mdr1a/b(-/-)/Bcrp(-/-) knockout (KO) mice, clearance was similar in WT (35.5 ± 16.7 mL/min/kg) and KO animals (22.0 ± 3.6 to 27.6 ± 5.2 mL/min/kg); oral exposure was also similar between WT and KO animals. After an oral 10 mg/kg dose of cobimetinib, the mean total brain to plasma ratio (Kp) at 6 h postdose was 0.3 and 0.2 in WT and Bcrp1(-/-) mice, resp. In Mdr1a/b(-/-) and Mdr1a/1b/Bcrp1(-/-) KO mice and WT mice treated with elacridar (a P-gp and BCRP inhibitor), Kp increased to 11, 6, and 7, resp. Increased brain exposure in Mdr1a/b(-/-) and Mdr1a/1b/Bcrp1(-/-) KO and elacridar treated mice was accompanied by up to ∼65% suppression of the target (pErk) in brain tissue, compared to WT mice. By MALDI imaging, the cobimetinib signal intensity was relatively high and was dispersed throughout the brain of Mdr1a/1b/Bcrp1(-/-) KO mice compared to low/undetectable signal intensity in WT mice. The efflux of cobimetinib by P-gp may have implications for the treatment of patients with brain tumors/metastases.
- 231(a) Choo, E. F.; Belvin, M.; Boggs, J.; Deng, Y.; Hoeflich, K. P.; Ly, J.; Merchant, M.; Orr, C.; Plise, E.; Robarge, K.; Martini, J. F.; Kassees, R.; Aoyama, R. G.; Ramaiya, A.; Johnston, S. H. Preclinical disposition of GDC-0973 and prospective and retrospective analysis of human dose and efficacy predictions Drug Metab. Dispos. 2012, 40, 919– 927 DOI: 10.1124/dmd.111.043778(b) Gilmartin, A. G.; Bleam, M. R.; Groy, A.; Moss, K. G.; Minthorn, E. A.; Kulkami, S. G.; Rominger, C. M.; Erskine, S.; Fisher, K. E.; Yang, J.; Azppacosta, F.; Annan, R.; Sutton, D.; Laquerre, S. G. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition Clin. Cancer Res. 2011, 17, 989– 1000 DOI: 10.1158/1078-0432.CCR-10-2200[Crossref], [PubMed], [CAS], Google Scholar231bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXis1eit7k%253D&md5=6154be5fa0afb034c6a5995508d7ea9eGSK1120212 (JTP-74057) Is an Inhibitor of MEK Activity and Activation with Favorable Pharmacokinetic Properties for Sustained In Vivo Pathway InhibitionGilmartin, Aidan G.; Bleam, Maureen R.; Groy, Arthur; Moss, Katherine G.; Minthorn, Elisabeth A.; Kulkarni, Swarupa G.; Rominger, Cynthia M.; Erskine, Symon; Fisher, Kelly E.; Yang, Jing-Song; Zappacosta, Francesca; Annan, Roland; Sutton, David; Laquerre, Sylvie G.Clinical Cancer Research (2011), 17 (5), 989-1000CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: Despite their preclin. promise, previous MEK inhibitors have shown little benefit for patients. This likely reflects the narrow therapeutic window for MEK inhibitors due to the essential role of the P42/44 MAPK pathway in many nontumor tissues. GSK1120212 is a potent and selective allosteric inhibitor of the MEK1 and MEK2 (MEK1/2) enzymes with promising antitumor activity in a phase I clin. trial (ASCO 2010). Our studies characterize GSK1120212' enzymic, cellular, and in vivo activities, describing its unusually long circulating half-life. Exptl. Design: Enzymic studies were conducted to det. GSK1120212 inhibition of recombinant MEK, following or preceding RAF kinase activation. Cellular studies examd. GSK1120212 inhibition of ERK1 and 2 phosphorylation (p-ERK1/2) as well as MEK1/2 phosphorylation and activation. Further studies explored the sensitivity of cancer cell lines, and drug pharmacokinetics and efficacy in multiple tumor xenograft models. Results: In enzymic and cellular studies, GSK1120212 inhibits MEK1/2 kinase activity and prevents Raf-dependent MEK phosphorylation (S217 for MEK1), producing prolonged p-ERK1/2 inhibition. Potent cell growth inhibition was evident in most tumor lines with mutant BRAF or Ras. In xenografted tumor models, GSK1120212 orally dosed once daily had a long circulating half-life and sustained suppression of p-ERK1/2 for more than 24 h; GSK1120212 also reduced tumor Ki67, increased p27Kip1/CDKN1B, and caused tumor growth inhibition in multiple tumor models. The largest antitumor effect was among tumors harboring mutant BRAF or Ras. Conclusions: GSK1120212 combines high potency, selectivity, and long circulating half-life, offering promise for successfully targeting the narrow therapeutic window anticipated for clin. MEK inhibitors.
- 232(a) Widemann, B. C.; Marcus, L. J.; Fisher, M. J.; Weiss, B. D.; Kim, A.; Dombi, E.; Baldwin, A.; Whitcomb, P.; Martin, S.; Gillespie, A.; Doyle, A. Phase I study of the MEK1/2 inhibitor selumetinib (AZ6244) hydrogen sulfate in children and young adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs) J. Clin. Oncol. 2014, 32 (Suppl.) 10018(b) https://clinicaltrials.gov/ct2/show/NCT01089101 (accessed June 12, 2016) .
- 233Binimetinib has advanced to a trial enrolling patients with brain cancer: https://clinicaltrials.gov/ct2/show/NCT02285439 (accessed June 10, 2016) .
- 234Iverson, C.; Larson, G.; Lai, C.; Yeh, L. T.; Dadson, C.; Weingarten, P.; Appleby, T.; Vo, T.; Maderna, A.; Vernier, J. M.; Hamatake, R.; Miner, J. N.; Quart, B. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer Cancer Res. 2009, 69, 6839– 6847 DOI: 10.1158/0008-5472.CAN-09-0679[Crossref], [PubMed], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVOmt7fF&md5=f12a941d012d72bb0efc8c4453dedd85RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of CancerIverson, Cory; Larson, Gary; Lai, Chon; Yeh, Li-Tain; Dadson, Claudia; Weingarten, Paul; Appleby, Todd; Vo, Todd; Maderna, Andreas; Vernier, Jean-Michel; Hamatake, Robert; Miner, Jeffrey N.; Quart, BarryCancer Research (2009), 69 (17), 6839-6847CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway provides numerous opportunities for targeted oncol. therapeutics. In particular, the MEK enzyme is attractive due to high selectivity for its target ERK and the central role that activated ERK plays in driving cell proliferation. The structural, pharmacol., and pharmacokinetic properties of RDEA119/BAY 869766, an allosteric MEK inhibitor, are presented. RDEA119/BAY 869766 is selectively bound directly to an allosteric pocket in the MEK1/2 enzymes. This compd. is highly efficacious at inhibiting cell proliferation in several tumor cell lines in vitro. In vivo, RDEA119/BAY 869766 exhibits potent activity in xenograft models of melanoma, colon, and epidermal carcinoma. RDEA119/BAY 869766 exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice. RDEA119/BAY 869766 shows a tissue selectivity that reduces its potential for central nervous system-related side effects. Using pharmacokinetic and pharmacodynamic data, we show that maintaining adequate MEK inhibition throughout the dosing interval is likely more important than achieving high peak levels because greater efficacy was achieved with more frequent but lower dosing. Based on its longer half-life in humans than in mice, RDEA119/BAY 869766 has the potential for use as a once- or twice-daily oral treatment for cancer. RDEA119/BAY 869766, an exquisitely selective, orally available MEK inhibitor, has been selected for clin. development because of its potency and favorable pharmacokinetic profile.
- 235Isshiki, Y.; Kohchi, Y.; Iikura, H.; Matsubara, Y.; Asoh, K.; Murata, T.; Kohchi, M.; Mizuguchi, E.; Tsujii, S.; Hattori, K.; Miura, T.; Yoshimura, Y.; Aida, S.; Miwa, M.; Saitoh, R.; Murao, N.; Okabe, H.; Belunis, C.; Janson, C.; Lukacs, C.; Schuck, V.; Shimma, N. Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent Bioorg. Med. Chem. Lett. 2011, 21, 1795– 1801 DOI: 10.1016/j.bmcl.2011.01.062
- 236Cohen, R. B.; Aamdal, S.; Nyakas, M.; Cavallin, M.; Green, D.; Learoyd, M.; Smith, I.; Kurzrock, R. A phase I dose-finding, safety and tolerability study of AZD8330 in patients with advanced malignancies Eur. J. Cancer 2013, 49, 1521– 1529 DOI: 10.1016/j.ejca.2013.01.013
- 237Shaw, J. V.; Zhang, H.; Carden, R.; Qiu, D.; Tian, H.; Ma, J.; Clark, A.; Ogden, J.; Goodstal, S. Abstract LB-456: Evaluation of brain pharmacokinetics as a potential differentiation factor for the MEK inhibitors, MSC2015103 and pimasertib Cancer Res. 2012, 72, LB-456 DOI: 10.1158/1538-7445.AM2012-LB-456
- 238Goutopoulos, A.; Askew, B.; Bankston, D.; Clark, A.; Dhanabal, M.; Dong, R.; Fischer, D.; Healey, B.; Jiang, X.; Josephson, K.; Lin, J.; Ma, J.; Noonan, T.; Qiu, D.; Rocha, C.; Romanelli, A.; Shutes, A.; Spooner, E.; Tian, H.; Yu, H. Abstract 4476: AS703026: a novel allosteric MEK inhibitor Cancer Res. 2009, 69 (Suppl.) 4776
- 239Shen, Y.; Boivin, R.; Yoneda, N.; Du, H.; Schiller, S.; Matsushima, T.; Goto, M.; Shirota, H.; Gusovsky, F.; Lemelin, C.; Jiang, Y.; Zhang, Z.; Pelletier, R.; Ikemori-Kawada, M.; Kawakami, Y.; Inoue, A. Discovery of anti-inflammatory clinical candidate E6201, inspired from resorcylic lactone LL-Z1640-2, III Bioorg. Med. Chem. Lett. 2010, 20, 3155– 3157 DOI: 10.1016/j.bmcl.2010.03.087
- 240Wu, J.; Nomoto, K.; Wang, J.; Kuznetsov, G.; Agoulnik, S.; Shuck, E.; Wong, N.; Towle, M.; Schnaderbeck, M.; Wu, S.; Littlefield, B. Abstract 3687: In vivo anticancer activity of E6201, a novel MEK1 inhibitor, against BRAF-mutated human cancer xenografts Cancer Res. 2009, 69 (Suppl.) 3687
- 241(a) Lee, C.; Fotovati, A.; Triscott, J.; Chen, J.; Venugopal, C.; Singhal, A.; Dunham, C.; Kerr, J. M.; Verreault, M.; Yip, S.; Wakimoto, H.; Jones, C.; Jayanthan, A.; Narendran, A.; Singh, S. K.; Dunn, S. E. Polo-like kinase 1 inhibition kills glioblastoma multiforme brain tumor cells in part through loss of SOX2 and delays tumor progression in mice Stem Cells 2012, 30, 1064– 1075 DOI: 10.1002/stem.1081(b) Danovi, D.; Folarin, A.; Gogolok, S.; Ender, C.; Elbatsh, A. M. O.; Engström, P. G.; Stricker, S. H.; Gagrica, S.; Georgian, A.; Yu, D.; U, K. P.; Harvey, K. J.; Ferretti, P.; Paddison, P. J.; Preston, J. E.; Abbott, N. J.; Bertone, P.; Smith, A.; Pollard, S. M. A high-content small molecule screen identifies sensitivity of glioblastoma stem cells to inhibition of polo-like kinase 1 PLoS One 2013, 8, e77053 DOI: 10.1371/journal.pone.0077053(c) Pezuk, J. A.; Brassesco, M. S.; Morales, A. G.; de Oliveira, J. C.; de Paula Queiroz, R. G.; Machado, H. R.; Carlotti, C. G.; Neder, L.; Scrideli, C. A.; Tone, L. G. Polo-like kinase 1 inhibition causes decreased proliferation by cell cycle arrest, leading to cell death in glioblastoma Cancer Gene Ther. 2013, 20, 499– 506 DOI: 10.1038/cgt.2013.46[Crossref], [PubMed], [CAS], Google Scholar241chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFKnu7jI&md5=bb21c197c08f06df5bf1bf0e8d28f187Polo-like kinase 1 inhibition causes decreased proliferation by cell cycle arrest, leading to cell death in glioblastomaPezuk, J. A.; Brassesco, M. S.; Morales, A. G.; de Oliveira, J. C.; de Paula Queiroz, R. G.; Machado, H. R.; Carlotti, C. G. Jr; Neder, L.; Scrideli, C. A.; Tone, L. G.Cancer Gene Therapy (2013), 20 (9), 499-506CODEN: CGTHEG; ISSN:0929-1903. (Nature Publishing Group)Glioblastoma (GBM) is one of the most aggressive central nervous system tumors with a patient's median survival of <1 yr. Polo-like kinases (PLKs) are a family of serine/threonine kinases that have key roles in cell cycle control and DNA-damage response. We evaluated PLK1, 2, 3 and 4 gene expression in 8 GBM cell lines and 17 tumor samples, and analyzed the effect of the PLK1 inhibition on SF188 and T98G GBM cell lines and 13 primary cultures. Our data showed PLK1 overexpression and a variable altered expression of PLK2, 3 and 4 genes in GBM tumor samples and cell lines. Treatments with nanomolar concns. of BI 2536, BI 6727, GW843682X or GSK461364 caused a significant decrease in GBM cells proliferation. Colony formation was also found to be inhibited (P<0.05), whereas apoptosis rate and mitotic index were significantly increased (P<0.05) after PLK1 inhibition in both GBM cell lines. Cell cycle anal. showed an arrest at G2 (P<0.05) and cell invasion was also decreased after PLK1 inhibition. Furthermore, simultaneous combinations of BI 2536 and temozolomide produced synergistic effects for both the cell lines after 48 h of treatment. Our findings suggest that PLK1 might be a promising target for the treatment of GBMs.(d) Tandle, A. T.; Kramp, T.; Kil, W. J.; Halthore, A.; Gehlhaus, K.; Shankavaram, U.; Tofilon, P. J.; Caplen, N. J.; Camphausen, K. Inhibition of polo-like kinase 1 in glioblastoma multiforme induces mitotic catastrophe and enhances radiosensitisation Eur. J. Cancer 2013, 49, 3020– 3028 DOI: 10.1016/j.ejca.2013.05.013(e) Pezuk, J. A.; Brassesco, M. S.; Morales, A. G.; de Oliveira, J. C.; de Oliveira, H. F.; Scrideli, C. A.; Tone, L. G. Inhibition of polo-like kinase 1 induces cell cycle arrest and sensitizes glioblastoma cells to ionizing radiation Cancer Biother.Radiopharm. 2013, 28, 516– 522 DOI: 10.1089/cbr.2012.1415[Crossref], [PubMed], [CAS], Google Scholar241ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Kht7jF&md5=64b00b16718879217b959eab70abdcd9Inhibition of Polo-Like Kinase 1 Induces Cell Cycle Arrest and Sensitizes Glioblastoma Cells to Ionizing RadiationPezuk, Julia Alejandra; Brassesco, Maria Sol; Morales, Andressa Gois; Carvalho de Oliveira, Jaqueline; Francisco de Oliveira, Harley; Scrideli, Carlos Alberto; Tone, Luiz GonzagaCancer Biotherapy and Radiopharmaceuticals (2013), 28 (7), 516-522CODEN: CBRAFJ; ISSN:1084-9785. (Mary Ann Liebert, Inc.)Despite efforts to improve surgical, radiol., and chemotherapeutic strategies, the outcome of patients with glioblastoma (GBM) is still poor. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays key roles in cell cycle control and has been assocd. with tumor growth and prognosis. Here, we aimed at testing the radiosensitizing effects of the PLK1 inhibitor BI 2536 on eight GBM cell lines. For cell cycle anal., T98G, U251, U343 MG-a, LN319, SF188, U138 MG, and U87 MG cell lines were treated with 10, 50, or 100 nM of BI 2536 for 24 h. In addn., cell cultures exposed to BI 2536 50 nM for 24 h were irradiated with γ-rays from 60Cobalt source at final doses of 2, 4, and 6 Gy. Combinatorial effects were evaluated through proliferation and clonogenic capacity assays. Treatment with BI 2536 caused mitotic arrest after 24 h, and increased apoptosis in GBM cells. Moreover, our results demonstrate that pretreatment with this drug sensitized six out of seven GBM cell lines to different doses of γ-irradn. as shown by decreased growth and abrogation of colony-formation capacity. Our data suggest that PLK1 blockage has a radiosensitizing effect on GBM, which could improve treatment strategies for this devastating tumor.(f) Triscott, J.; Lee, C.; Foster, C.; Manoranjan, B.; Pamid, M. R.; Berns, R.; Fotovati, A.; Venugopal, C.; O’Halloran, K.; Narendran, A.; Hawkins, C.; Ramaswamy, V.; Bouffet, E.; Taylor, M. D.; Singhal, A.; Hukin, J.; Rassekh, R.; Yip, S.; Northcott, P.; Singh, S. K.; Dunham, C.; Dunn, S. Personalizing the treatment of pediatric medulloblastoma: polo-like kinase 1 as a molecular target in high-risk children Cancer Res. 2013, 73, 6734– 6744 DOI: 10.1158/0008-5472.CAN-12-4331
- 242(a) Markant, S. L.; Esparza, L. A.; Sun, J.; Barton, K. L.; McCoig, L. M.; Grant, G. A.; Crawford, J. R.; Levy, M. L.; Northcott, P. A.; Shih, D.; Remke, M.; Taylor, M. D.; Wechsler-Reya, R. J. Targeting sonic hedgehog-associated medulloblastoma through inhibition of aurora and polo-like kinases Cancer Res. 2013, 73, 6310– 6322 DOI: 10.1158/0008-5472.CAN-12-4258(b) Barton, V. N.; Foreman, N. K.; Donson, A. M.; Birks, D. K.; Handler, M. H.; Vibhakar, R. Aurora kinase A as a rational target for therapy in glioblastoma J. Neurosurg. Pediatr. 2010, 6, 98– 105 DOI: 10.3171/2010.3.PEDS10120[Crossref], [PubMed], [CAS], Google Scholar242bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cnktlagsw%253D%253D&md5=58271fedc8396c9e1a856991991b30e2Aurora kinase A as a rational target for therapy in glioblastomaBarton Valerie N; Foreman Nicholas K; Donson Andrew M; Birks Diane K; Handler Michael H; Vibhakar RajeevJournal of neurosurgery. Pediatrics (2010), 6 (1), 98-105 ISSN:.OBJECT: Despite advances in the knowledge of tumor biology, the outcome of glioblastoma tumors remains poor. The design of many molecularly targeted therapies in glioblastoma has focused on inhibiting molecular abnormalities present in tumor cells compared with normal tissue rather than patient outcome-associated factors. As an alternative approach, the present study identified genes associated with shorter survival as potential therapeutic targets. It was hypothesized that inhibition of a molecular target associated with poor outcome would impact glioblastoma cell proliferation. METHODS: The present study correlated patient survival data with tumor gene expression profiling and gene ontology analysis. Genes associated with shorter survival were identified and one of these was selected for therapeutic targeting in an in vitro system. Glioblastoma cell growth suppression was measured by H(3)-thymidine uptake, colony formation, and flow cytometry. RESULTS: The gene expression microarray and ontology analysis revealed that genes involved in mitotic processes, including AURKA, were associated with poor prognosis in glioblastoma. Inhibition of AURKA suppressed glioblastoma cell growth. Moreover, inhibition of AURKA was synergistic with radiation in glioblastoma cells at high radiation doses. CONCLUSIONS: Relative expression of AURKA may be of prognostic value and warrants further investigation with larger, prospective studies. Pharmacological inhibition of AURKA is a potentially promising therapy for glioblastoma.(c) Klein, A.; Reichardt, W.; Jung, V.; Zang, K. D.; Meese, E.; Urbschat, S. Overexpression and amplification of STK15 in human gliomas Int. J. Oncol. 2004, 25, 1789– 1794 DOI: 10.3892/ijo.25.6.1789[Crossref], [PubMed], [CAS], Google Scholar242chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhsVyjsw%253D%253D&md5=c7541c7f1d229f6794d3278dedb828cbOverexpression and amplification of STK15 in human gliomasKlein, Alexandra; Reichardt, Wilfried; Jung, Volker; Zang, Klaus D.; Meese, Eckart; Urbschat, SteffiInternational Journal of Oncology (2004), 25 (6), 1789-1794CODEN: IJONES; ISSN:1019-6439. (International Journal of Oncology)The serine/threonine kinase 15 (STK15) at chromosome 20q13.2 is frequently shown to be amplified and overexpressed in several human cancers. STK15 was reported to act as a cell cycle regulator and its overexpression induces centrosome amplification and aneuploidy. Recently the authors showed that STK15 even plays a role in human malignant brain tumors and the authors described an amplification of the gene in 31% of the investigated gliomas. In this study the authors scrutinized the correlation of increased STK15 on DNA and mRNA levels in gliomas of different histol. grades. Southern blotting confirmed the amplification frequency of the STK15 gene, which had been previously detected by comparative PCR. In total, DNA gains were found in 26% of the investigated gliomas. Interestingly, the authors detected overexpression of STK15 mRNA in 60% of the analyzed brain tumors. The elevated expression does not strongly correlate with gains on DNA level, but all cases with an amplification of the STK15 gene display overexpression. Gains of the STK15 gene seem to occur irresp. of the histol. grades of the tumors, so that STK15 probably is not a progression assocd. factor. Amplification and overexpression of the kinase rather represent a primary alteration in human gliomas, which could play an important role as an early event in all glioma subtypes.
- 243Li, N.; Maly, D. J.; Chanthery, Y. H.; Sirkis, D. W.; Nakamura, J. L.; Berger, M. S.; James, C. D.; Shokat, K. M.; Weiss, W. A.; Persson, A. I. Radiotherapy followed by aurora kinase inhibition targets tumor-propagating cells in human glioblastoma Mol. Cancer Ther. 2015, 14, 419– 428 DOI: 10.1158/1535-7163.MCT-14-0526[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitlOjsbg%253D&md5=a4c7daceb8c770e4cfb64d5b1bbeba61Radiotherapy Followed by Aurora Kinase Inhibition Targets Tumor-Propagating Cells in Human GlioblastomaLi, Nan; Maly, Dustin J.; Chanthery, Yvan H.; Sirkis, Daniel W.; Nakamura, Jean L.; Berger, Mitchel S.; James, C. David; Shokat, Kevan M.; Weiss, William A.; Persson, Anders I.Molecular Cancer Therapeutics (2015), 14 (2), 419-428CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Glioblastoma (GBM) is the most common malignant primary brain tumor. Radiotherapy fails to eliminate subpopulations of stem-like tumor-propagating cells (TPC), resulting in tumor regrowth. To identify kinases that promote TPC self-renewal rather than increasing proliferation in human GBM cultures, we screened a library of 54 nonselective tool compds. and detd. their kinase inhibitor profiles in vitro. Most compds. inhibited aurora kinase (AURK) activity and blocked TPC self-renewal, while inducing GBM cell polynucleation and apoptosis. To prevent regrowth by TPCs, we used a priming dose of radiation followed by incubation with the pan-AURK inhibitor VX680 to block self-renewal and induce apoptosis in GBM cultures. In mice xenografted with human GBM cells, radiotherapy followed by VX680 treatment resulted in reduced tumor growth and increased survival relative to either monotherapy alone or VX680 treatment before radiation. Our results indicate that AURK inhibition, subsequent to radiation, may enhance the efficacy of radiotherapy by targeting radioresistant TPCs in human GBMs. Mol Cancer Ther; 14(2); 419-28. ©2014 AACR.
- 244Wu, C.-P.; Hsieh, C.-H.; Hsiao, S.-H.; Luo, S.-Y.; Su, C.-Y.; Li, Y.-Q.; Huang, Y.-H.; Huang, C.-W.; Hsu, S.-C. Human ATP-binding cassette transporter ABCB1 confers resistance to volasertib (BI6727), a selective inhibitor of polo-like kinase 1 Mol. Pharmaceutics 2015, 12, 3885– 3895 DOI: 10.1021/acs.molpharmaceut.5b00312[ACS Full Text], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFKiu7rI&md5=57e74ce734e224b5e5da848c87d8ea7cHuman ATP-Binding Cassette Transporter ABCB1 Confers Resistance to Volasertib (BI 6727), a Selective Inhibitor of Polo-like Kinase 1Wu, Chung-Pu; Hsieh, Chia-Hung; Hsiao, Sung-Han; Luo, Shi-Yu; Su, Ching-Ya; Li, Yan-Qing; Huang, Yang-Hui; Huang, Chiun-Wei; Hsu, Sheng-ChiehMolecular Pharmaceutics (2015), 12 (11), 3885-3895CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)The overexpression of the serine/threonine specific polo-like kinase 1 (Plk1) is assocd. with poor prognosis in many types of cancer. Consequently, Plk1 has emerged as a valid therapeutic target for anticancer drug design. Volasertib is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting cell cycle arrest at nanomolar concns. However, the risk of developing drug resistance, which is often assocd. with the overexpression of the ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein), can present a therapeutic challenge for volasertib and many other therapeutic drugs. Although volasertib is highly effective against the proliferation of numerous cancer cell lines, the authors found that the overexpression of ABCB1 in cancer cells leads to cellular resistance to volasertib and reduces the level of volasertib-stimulated G2/M cell cycle arrest and subsequent onset of apoptosis. Furthermore, the authors demonstrate that volasertib competitively inhibits the function of ABCB1 and stimulates the basal ATPase activity of ABCB1 in a concn.-dependent manner, which is consistent with substrate transport by ABCB1. More importantly, the authors discovered that the coadministration of an inhibitor or drug substrate of ABCB1 restored the anticancer activity of volasertib in ABCB1-overexpressing cancer cells. In conclusion, the results of the authors' study reveal that ABCB1 neg. affects the efficacy of volasertib and supports its combination with a modulator of ABCB1 to improve clin. responses.
- 245Wu, C.-P.; Hsiao, S.-H.; Sim, H.-M.; Luo, S.-Y.; Tuo, W.-C.; Cheng, H.-W.; Li, Y.-Q.; Huan, Y.-H.; Ambudkar, S. V. Human ABCB1 (P-glycoprotein) and ABCG2 mediate resistance to BI 2536, a potent and selective inhibitor of polo-like kinase 1 Biochem. Pharmacol. 2013, 86, 904– 913 DOI: 10.1016/j.bcp.2013.08.004
- 246Wu, C.-P.; Hsiao, S.-H.; Luo, S.-Y.; Tuo, W.-C.; Su, C.-Y.; Li, Y.-Q.; Huang, Y.-H.; Hsieh, C. H. Overexpression of human ABCB1 in cancer cells leads to reduced activity of GSK461364, a specific inhibitor of polo-like kinase 1 Mol. Pharmaceutics 2014, 11, 3727– 3736 DOI: 10.1021/mp500492r[ACS Full Text], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVykurrE&md5=91eda9381c54d0d848bb0867a4b7f167Overexpression of Human ABCB1 in Cancer Cells Leads to Reduced Activity of GSK461364, a Specific Inhibitor of Polo-like Kinase 1Wu, Chung-Pu; Hsiao, Sung-Han; Luo, Shi-Yu; Tuo, Wei-Cherng; Su, Ching-Ya; Li, Yan-Qing; Huang, Yang-Hui; Hsieh, Chia-HungMolecular Pharmaceutics (2014), 11 (10), 3727-3736CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Polo-like kinase 1 (Plk1) is a serine/threonine kinase involved in the regulation of mitosis and is overexpressed in many tumor types. Inhibition of Plk1 leads to cell cycle arrest, onset of apoptosis, and cell death, thus Plk1 has emerged as an important target for cancer treatment. GSK461364 is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting G2/M cell cycle arrest at low concns. However, as is the case for many therapeutic drugs, the risk of developing drug resistance to GSK461364 can present a therapeutic challenge to clinicians. Since the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 is one of the most common mechanisms of drug resistance, we aimed to investigate the effect of ABCB1 on the cellular efficacy of GSK461364. In this study, we obsd. a significantly reduced activity of GSK461364 in cells overexpressing human ABCB1. We showed that GSK461364 stimulates the ABCB1 ATPase activity and competitively inhibits ABCB1-mediated efflux of calcein-AM in a concn.-dependent manner. Moreover, as a way to assess the impact of ABCB1 on the efficacy of GSK461364, we evaluated the G2/M cell cycle arrest and apoptosis induced by GSK461364. We discovered that, by inhibiting the function of ABCB1, the reduced G2/M cell cycle arrest, apoptosis, and sensitivity to GSK461364 treatment in ABCB1-overexpressing cells can be significantly restored. In conclusion, in order to achieve a better therapeutic outcome, combination therapy of GSK461364 with a modulator of ABCB1 should be further investigated as a potential treatment approach.
- 247White, M. P.; Babayeva, M.; Taft, D. R.; Maniar, M. Determination of intestinal permeability of rigosertib (ON 01910.Na, Estybon): correlation with systemic exposure J. Pharm. Pharmacol. 2013, 65, 960– 969 DOI: 10.1111/jphp.12057[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVCht77O&md5=e4b69c7551347aec1f8128561cc741fcDetermination of intestinal permeability of rigosertib (ON 01910.Na, Estybon): correlation with systemic exposureWhite, Michael P.; Babayeva, Mariana; Taft, David R.; Maniar, ManojJournal of Pharmacy and Pharmacology (2013), 65 (7), 960-969CODEN: JPPMAB; ISSN:0022-3573. (John Wiley & Sons Ltd.)Rigosertib (ON 01910.Na, Estybon) is a novel, anticancer agent undergoing phase 3 clin. trials for a lead indication against myelodysplastic syndromes (MDS). In this research, the permeability of rigosertib was evaluated using the in-situ perfused rat intestine (IPRI) model to support development of an oral formulation for rigosertib for treating cancer patients. Expts. (n = 6 per group) were conducted using male Sprague-Dawley rats. Studies evaluated permeability across various intestinal segments and assessed the dose-linearity of absorption over the entire intestinal length. Drug concns. in the portal and jugular vein were collected to correlate permeability parameters with presystemic and systemic exposure. Rigosertib permeability was highest in the jejunum, although parameter ests. indicated that rigosertib was a medium permeability compd. The compd. displayed nonlinear absorption in the IPRI model, suggesting a saturable transport process. Transport inhibition studies using Caco-2 cells demonstrated that rigosertib was a P-glycoprotein (P-gp) substrate. Abs. bioavailability of rigosertib (10 and 20 mg/kg, 1-h infusion) in rats was estd. to be 10-15%. However, the fraction absorbed in humans predicted from IPRI data (52%) was consistent with published clin. data for rigosertib (35% oral bioavailability). The results of this research indicated that rigosertib is a promising candidate for oral delivery. Further studies are needed to evaluate the potential impact of P-gp and other intestinal transporters on the oral absorption of this promising anticancer agent.
- 248Sero, V.; Tavanti, E.; Vella, S.; Hattinger, C. M.; Fanelli, M.; Michelacci, F.; Versteeg, R.; Valsasina, B.; Gudeman, B.; Picci, P.; Serra, M. Targeting polo-like kinase 1 by NMS-P937 in osteosarcoma cell lines inhibits tumor cell growth and partially overcomes drug resistance Invest. New Drugs 2014, 32, 1167– 1180 DOI: 10.1007/s10637-014-0158-6
- 249Nie, Z.; Feher, V.; Natala, S.; McBride, C.; Kiryanov, A.; Jones, B.; Lam, B.; Liu, Y.; Kaldor, S.; Stafford, J.; Hikami, K.; Uchiyama, N.; Kawamoto, T.; Hikichi, Y.; Matsumoto, S.; Amano, N.; Zhang, L.; Hosfield, D.; Skene, R.; Zou, H.; Cao, X.; Ichikawa, T. Discovery of TAK-960: an orally available small molecule inhibitor of polo-like kinase 1 (PLK1) Bioorg. Med. Chem. Lett. 2013, 23, 3662– 3666 DOI: 10.1016/j.bmcl.2013.02.083[Crossref], [PubMed], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnsVyksr0%253D&md5=25dca079405c47098fd261a77ceccf53Discovery of TAK-960: An orally available small molecule inhibitor of polo-like kinase 1 (PLK1)Nie, Zhe; Feher, Victoria; Natala, Srinivasa; McBride, Christopher; Kiryanov, Andre; Jones, Benjamin; Lam, Betty; Liu, Yan; Kaldor, Stephen; Stafford, Jeffrey; Hikami, Kouki; Uchiyama, Noriko; Kawamoto, Tomohiro; Hikichi, Yuichi; Matsumoto, Shin-ichi; Amano, Nobuyuki; Zhang, Lilly; Hosfield, David; Skene, Robert; Zou, Hua; Cao, Xiaodong; Ichikawa, TakashiBioorganic & Medicinal Chemistry Letters (2013), 23 (12), 3662-3666CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Using structure-based drug design, the authors identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960 (I). TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.
- 250Cheung, C. H. A.; Sarvagalla, S.; Lee, J. Y. C.; Huang, Y. C.; Coumar, M. S. Aurora kinase inhibitor patents and agents in clinical testing: an update (2011–2013) Expert Opin. Ther. Pat. 2014, 24, 1021– 1038 DOI: 10.1517/13543776.2014.931374[Crossref], [PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlKjtb3E&md5=20cc080521ab567ec3804e9beb5e505cAurora kinase inhibitor patents and agents in clinical testing: an update (2011 - 2013)Cheung, Chun Hei Antonio; Sarvagalla, Sailu; Lee, Jane Ying-Chieh; Huang, Yi-Chun; Coumar, Mohane SelvarajExpert Opinion on Therapeutic Patents (2014), 24 (9), 1021-1038CODEN: EOTPEG; ISSN:1354-3776. (Informa Healthcare)A review. Introduction: Aurora kinase A, B and C, members of serine/threonine kinase family, are key regulators of mitosis. As Aurora kinases are overexpressed in many of the human cancers, small-mol. inhibitors of Aurora kinase have emerged as a possible treatment option for cancer. Areas covered: In 2009 and 2011, the literature pertaining to Aurora kinase inhibitors and their patents was reviewed. Here, the aim is to update the information for Aurora kinase inhibitors in clin. trials and the patents filed between the years 2011 and 2013. Pubmed, Scopus, Scifinder, USPTO, EPO and www.clinicaltrials.gov databases were used for searching the literature and patents for Aurora kinase inhibitors. Expert opinion: Even though both Aurora sub-type selective as well as pan-selective inhibitors show preclin. and clin. efficacy, so far no Aurora kinase inhibitor has been approved for clin. use. Particularly, dose-limiting toxicity (neutropenia) is a key issue that needs to be addressed. Preliminary evidence suggests that the use of selective Aurora A inhibitors could avoid Aurora B-mediated neutropenia in clin. settings. Also, use of adjunctive agents such as granulocyte stimulating factor to overcome neutropenia assocd. with Aurora B inhibition could be an answer to overcome the toxicity and bring Aurora inhibitors to market in the future.
- 251Van Brocklyn, J. R.; Wojton, J.; Meisen, W. H.; Kellough, D. A.; Ecsedy, J. A.; Kaur, B.; Lehman, N. L. Aurora-A inhibition offers a novel therapy effective against intracranial glioblastoma Cancer Res. 2014, 74, 5364– 5370 DOI: 10.1158/0008-5472.CAN-14-0386
- 252Sathornsumetee, S.; Reardon, D. A.; Desjardins, A.; Quinn, J. A.; Vredenburgh, J. J.; Rich, J. N. Molecularly targeted therapy for malignant glioma Cancer 2007, 110, 13– 24 DOI: 10.1002/cncr.22741
- 253Mochly-Rosen, D.; Das, K.; Grimes, K. V. Protein kinase C, an elusive target? Nat. Rev. Drug Discovery 2012, 11, 937– 957 DOI: 10.1038/nrd3871
- 254(a) Kreisl, T. N.; Kotliarova, S.; Butman, J. A.; Albert, P. S.; Kim, L.; Musib, L.; Thornton, D.; Fine, H. A. A phase I/II trial of enzastaurin in pateints with recurrent high-grade gliomas Neuro-Oncology 2010, 12, 181– 189 DOI: 10.1093/neuonc/nop042(b) Wick, W.; Puduvalli, V. K.; Chamberlain, M. C.; van den Bent, M. J.; Carpentier, A. F.; Cher, L. M.; Mason, W.; Weller, M.; Hong, S.; Musib, L.; Liepa, A. M.; Thornton, D. E.; Fine, H. A. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma J. Clin. Oncol. 2010, 28, 1168– 1174 DOI: 10.1200/JCO.2009.23.2595[Crossref], [PubMed], [CAS], Google Scholar254bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXktF2ltb4%253D&md5=ac3cf8f3fc54dd6bbd6ef01866bbda0fPhase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastomaWick, Wolfgang; Puduvalli, Vinay K.; Chamberlain, Marc C.; van den Bent, Martin J.; Carpentier, Antoine F.; Cher, Lawrence M.; Mason, Warren; Weller, Michael; Hong, Shengyan; Musib, Luna; Liepa, Astra M.; Thornton, Donald E.; Fine, Howard A.Journal of Clinical Oncology (2010), 28 (7), 1168-1174CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Purpose: This phase III open-label study compared the efficacy and safety of enzastaurin vs. lomustine in patients with recurrent glioblastoma (WHO grade 4). Patients and Methods: Patients were randomly assigned 2:1 to receive 6-wk cycles of enzastaurin 500 mg/d (1,125-mg loading dose, day 1) or lomustine (100 to 130 mg/m2, day 1). Assuming a 45% improvement in progression-free survival (PFS), 397 patients were required to provide 80% power to achieve statistical significance at a one-sided level of .025. Results: Enrollment was terminated at 266 patients (enzastaurin, n = 174; lomustine, n = 92) after a planned interim anal. for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 mo; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 mo; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-mo PFS rate (P = .13) did not differ significantly between enzastaurin and lomustine, resp. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, resp. Time to deterioration of phys. and functional well-being and symptoms did not differ between arms (HR = 1.12; P = .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematol. toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P ≤ .001). Conclusion: Enzastaurin was well tolerated and had a better hematol. toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma.
- 255Gronberg, B. H.; Ciuleanu, T.; Flotten, O.; Knuuttila, A.; Abel, E.; Langer, S. W.; Krejcy, K.; Liepa, A. M.; Munoz, M.; Hahka-Kemppinen, M.; Sundstrom, S. A placebo-controlled, randomized phase II study of maintenance enzastaurin following whole brain radiation therapy in the treatment of brain metastases from lung cancer Lung Cancer 2012, 78, 63– 69 DOI: 10.1016/j.lungcan.2012.07.007
- 256Yasoshima, K.; Kuwabara, T.; Fuse, E.; Kuramitu, T.; Kurata, N.; Nishiie, H.; Oishi, T.; Kobayashi, H.; Kobayashi, S. Pharmacokinetics, distribution, metabolism and excretion of [3H]UCN-01 in rats and dogs after intravenous administration Cancer Chemother. Pharmacol. 2001, 47, 106– 112 DOI: 10.1007/s002800000213[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhsFSgtbc%253D&md5=7c92233a09c08beb24146c9d03a853c1Pharmacokinetics, distribution, metabolism and excretion of [3H]UCN-01 in rats and dogs after intravenous administrationYasoshima, Kenichi; Kuwabara, Takashi; Fuse, Eiichi; Kuramitu, Tomoko; Kurata, Noriaki; Nishiie, Hiroyoshi; Oishi, Takayoshi; Kobayashi, Hiroyuki; Kobayashi, SatoshiCancer Chemotherapy and Pharmacology (2001), 47 (2), 106-112CODEN: CCPHDZ; ISSN:0344-5704. (Springer-Verlag)Purpose: To evaluate the metabolic fate of UCN-01, a signal transduction inhibitor, blood and plasma concns., distribution, metab. and excretion were investigated in rats and dogs after i.v. administration of [3H]UCN-01. Methods: The radioactivity in plasma, blood and tissues was measured after i.v. administration of UCN-01. In addn., the radioactivity excreted in bile, urine and feces was also detd. Results: The radioactivity in rat and dog plasma disappeared triphasically with terminal half-lives of 21.3 and 27.2 h, resp. The ratios of the blood-to-plasma concns. ranged from 0.82 to 1.13 in rats and 0.81 to 1.73 in dogs. From 0.5 to 4 h after giving [3H]UCN-01 to rats, the radioactivity in all tissues except the brain and testes was higher than in plasma. The highest concn. was obsd. in the lungs followed by the liver and kidneys. The radioactivity was mainly excreted in feces, reaching 96.0% of the radioactivity dose in rats and 78.4% in dogs up to 168 h after injection. Since the biliary excreted radioactivity was 67.2% over 48 h in bile duct-cannulated rats, most of the radioactivity excreted in feces was from biliary radioactivity. There were several metabolites in bile samples, but little UCN-01. Conclusions: UCN-01 is mainly eliminated by the liver, and there are high concns. of radioactivity derived from [3H]UCN-01 in all tissues except the brain and testes.
- 257Budworth, J.; Davies, R.; Malkhandi, J.; Gant, T. W.; Ferry, D. R.; Gescher, A. Comparison of staurosporine and four analogues: their effects on growth, rhodamine 123 retention and binding to P-glycoprotein in multidrug-resistance MCF-7/Adr cells Br. J. Cancer 1996, 73, 1063– 1068 DOI: 10.1038/bjc.1996.205[Crossref], [PubMed], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjtlSiurw%253D&md5=7aa79db6a7c1e0793d938f69835b5d8cComparison of staurosporine and four analogs: Their effects on growth, rhodamine 123 retention and binding to P-glycoprotein in multidrug-resistant MCF-7/Adr cellsBudworth, J.; Davies, R.; Malkhandi, J.; Gant, T. W.; Ferry, D. R.; Gescher, A.British Journal of Cancer (1996), 73 (9), 1063-1068CODEN: BJCAAI; ISSN:0007-0920. (Stockton)The potent kinase inhibitor staurosporine and its protein kinase C (PKC)-selective analog CGP 41251 are known to sensitize cells with the multidrug resistance (MDR) phenotype mediated by P-glycoprotein (P-gp) to cytotoxic agents. Here four PKC-selective staurosporine congeners, CGP 41251, UCN-01, RO 31 8220 and GF 109203X, were compared with staurosporine in terms of their MDR-reversing properties and their susceptibility towards P-gp-mediated drug efflux from MCF-7/Adr cells. Staurosporine was the most potent and the bisindolylmaleimides RO 31 8220 and GF 109203X the least potent cytostatic agents. When compared with MCF-7 wild-type cells, MCF-7/Adr cells were resistant towards the growth-arresting properties of RO 31 8220 and UCN-01, with resistance ratios of 12.6 and 7.0 resp. This resistance could be substantially reduced by inclusion of the P-gp inhibitor reserpine. The ratios for GF 109203X, staurosporine and CGP 41251 were 1.2, 2.0 and 2.9 resp., and they were hardly affected by reserpine. These results suggest that RO 31 8220 and UCN-01 are avidly transported by P-gp but that the other compds. are not. Staurosporine and CGP 41251 at 10 and 20 nM, resp., decreased efflux of the P-gp probe rhodamine 123 (R123) from MCF-7/Adr cells, whereas RO 31 8220 and GF 109203X at 640 nM were inactive. CGP 41251 was the most effective and GF 109203X the least effective inhibitor of equil. binding of [3H]vinblastine to its specific binding sites, probably P-gp, in MCF-7/Adr cells. Overall, the results imply that for this class of compd. the structural properties that det. susceptibility towards P-gp-mediated substrate transport are complex. Comparison with ability to inhibit PKC suggests that the kinase inhibitors affect P-gp directly and not via inhibition of PKC. Among these compds. CGP 41251 was a very potent MDR-reversing agent with high affinity for P-gp and least affected by P-gp-mediated resistance, rendering it an attractive drug candidate for clin. development.
- 258Capdeville, R.; Buchdunger, E.; Zimmerman, J.; Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug Nat. Rev. Drug Discovery 2002, 1, 493– 502 DOI: 10.1038/nrd839[Crossref], [PubMed], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XkvFKlurY%253D&md5=c8f6b7a66f74b64f0dedb5e641097accGlivec (STI571, imatinib), a rationally developed, targeted anticancer drugCapdeville, Renaud; Buchdunger, Elisabeth; Zimmermann, Juerg; Matter, AlexNature Reviews Drug Discovery (2002), 1 (7), 493-502CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. In the early 1980s, it became apparent that the work of pioneers such as Robert Weinberg, Mariano Barbacid and many others in identifying cancer-causing genes in humans was opening the door to a new era in anticancer research. Motivated by this, and by dissatisfaction with the limited efficacy and tolerability of available anticancer modalities, a drug discovery program was initiated with the aim of rationally developing targeted anticancer therapies. Here, we describe how this program led to the discovery and continuing development of Glivec (Gleevec in the United States), the first selective tyrosine-kinase inhibitor to be approved for the treatment of a cancer.
- 259Quintas-Cardama, A.; Kantarjian, H. M.; Cortes, J. E. Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia Cancer Control 2009, 16, 122– 131
- 260Leis, J. F.; Stepan, D. E.; Curtin, P. T.; Ford, J. M.; Peng, B.; Schubach, S.; Druker, B. J.; Mariarz, R. T. Central nervous system failure in patients with chroinic mylogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571) Leuk. Lymphoma 2004, 45, 695– 698 DOI: 10.1080/10428190310001625728[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpvV2lsLg%253D&md5=f9279095aa2f10646f3a40e72a904170Central Nervous System Failure in Patients with Chronic Myelogenous Leukemia Lymphoid Blast Crisis and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Treated with Imatinib (STI-571)Leis, Jose; Stepan, Daniel; Curtin, Peter; Ford, John; Peng, Bin; Schubach, Susan; Druker, Brian; Maziarz, RichardLeukemia & Lymphoma (2004), 45 (4), 695-698CODEN: LELYEA; ISSN:1042-8194. (Taylor & Francis Ltd.)Isolated central nervous system (CNS) relapse occurred in 5 out of 24 patients (20.8%) with chronic myeloid leukemia (CML) lymphoid blast crisis (2), Philadelphia (Ph) chromosome pos. acute lymphoblastic leukemia (ALL) (2) or CML with biphenotypic markers (1) treated on imatinib mesylate (IM) protocols at our institution. CNS relapse occurred despite peripheral blood (5) and bone marrow (3) complete responses. Median time to CNS relapse was day 32 (range 23 to 100). This observation raised the possibility that IM may not penetrate into the CNS. Simultaneous plasma and cerebral spinal fluid (CSF) IM levels were detd. in four subsequent patients by liq. chromatog. and mass spectrophotometric assay. Levels of IM were found to be approx. two logs lower in CSF than in plasma (0.044 μg/mL (0.088±0.029 μM) vs. 3.27 μg/mL (6.54±0.93 μM)). CSF levels were substantially below the concn. required for inhibition of BCR-ABL and killing of cell lines in vitro. These results suggest that IM may not penetrate the intact blood/brain barrier and its implications are discussed.
- 261(a) Dai, H.; Marbach, P.; Lemaire, M.; Hayes, M.; Elmquist, W. F. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux J. Pharmacol. Exp. Ther. 2003, 304, 1085– 1092 DOI: 10.1124/jpet.102.045260[Crossref], [PubMed], [CAS], Google Scholar261ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXit1eisrs%253D&md5=c4f1082f27454e16635d768ce337ce7fDistribution of STI-571 to the brain is limited by P-glycoprotein-mediated effluxDai, Haiqing; Marbach, Peter; Lemaire, Michel; Hayes, Michael; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2003), 304 (3), 1085-1092CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)The adequate distribution of STI-571 (Gleevec) to the central nervous system (CNS) is crit. for its effective use in CNS tumors. P-glycoprotein-mediated efflux in the blood-brain barrier may play a role in the CNS delivery of this drug. Whether STI-571 is a substrate of P-glycoprotein was detd. by examg. the directional flux of [14C]STI-571 in parental and MDR1-transfected Madin-Darby canine kidney (MDCK) II epithelial cell monolayers. The basolateral-to-apical flux of STI-571 was 39-fold greater than the apical-to-basolateral flux in the MDR1-transfected cells and 8-fold greater in the parental cell monolayers. This difference in directional flux was significantly reduced by a specific P-glycoprotein inhibitor (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzo- suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (LY335979). The role of P-glycoprotein in the CNS distribution of STI-571 was examd. in vivo, using wild-type and mdr1a/b (-/-) knockout mice that were orally administered 25 mg/kg [14C]STI-571. In the wild-type mice, the brain-to-plasma STI-571 concn. ratio at all time points was low (1-3%); however, there was an 11-fold greater brain partitioning of STI-571 at 1 h postdose in the mdr1a/b (-/-) mice compared with the wild-type mice. When 12.5 mg/kg STI-571 was given i.v., the brain-to-plasma ratio of STI-571 in the mdr1a/b (-/-) mice was approx. 7-fold greater than that of wild-type mice up to 120 min postdose. These data indicate that STI-571 is a substrate of P-glycoprotein, and that the inhibition of P-glycoprotein affects the transport of STI-571 across MDCKII monolayers. Moreover, P-glycoprotein plays an important role in limiting the distribution of STI-571 to the CNS.(b) Breedveld, P.; Pluim, D.; Cipriani, G.; Wielinga, P.; van Tellingen, O.; Schinkel, A. H.; Schellens, J. H. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients Cancer Res. 2005, 65, 2577– 2582 DOI: 10.1158/0008-5472.CAN-04-2416(c) Rajappa, S.; Uppin, S. G.; Raghunadharao, D.; Rao, I. S.; Surath, A. Isolated central nervous system blast crisis in chronic myeloid leukemia Hematol. Oncol. 2004, 22, 179– 181 DOI: 10.1002/hon.737[Crossref], [PubMed], [CAS], Google Scholar261chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MvnsF2kug%253D%253D&md5=62855c254a97c7fc51884e685aa4bd39Isolated central nervous system blast crisis in chronic myeloid leukemiaRajappa Senthil; Uppin Shantveer G; Raghunadharao D; Rao I Satish; Surath AnjnaHematological oncology (2004), 22 (4), 179-81 ISSN:0278-0232.Chronic myeloid leukemia is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome, t(9:22). Extramedullary blast crisis is a rare event. Imatinib mesylate has become the treatment of choice, especially for patients for whom allogenic stem cell transplantation is not an option. Imatinib produces complete cytogenetic responses in excess of 80%. However, the penetration of the drug and its metabolites into the CNS (Central Nervous System) is poor. Hence for patients who are on prolonged imatinib therapy and continue to have complete cytogenetic responses, the central nervous system may become a sanctuary site. We report a patient who had a complete hematologic and cytogenetic response and presented with headache and vomiting. The MRI showed meningeal enhancement and the CSF (Cerebro Spinal Fluid) examination was positive for blasts. He was started on cranial radiotherapy and triple intrathecal chemotherapy. He showed good symptomatic improvement and cleared the blasts in the CSF. At the end of radiation, he was in complete hematological remission but had 50% marrow metaphases positive for Philadelphia chromosome. As he did not have a matched sibling donor, the dose of imatinib was increased to 600 mg daily. He continues to be in complete hematologic remission at the time of this report.(d) Neville, K.; Parise, R. A.; Thompson, P.; Aleksic, A.; Egorin, M. J.; Balis, F. M.; McGuffey, L.; McCully, C.; Berg, S. L.; Blaney, S. M. Plasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primates Clin. Cancer Res. 2004, 10, 2525– 2529 DOI: 10.1158/1078-0432.CCR-03-0155[Crossref], [PubMed], [CAS], Google Scholar261dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXivFSqsbo%253D&md5=1849626bb417a9aaa5b6b6e13c45bc5cPlasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primatesNeville, Kathleen; Parise, Robert A.; Thompson, Patrick; Aleksic, Alexander; Egorin, Merrill J.; Balis, Frank M.; McGuffey, Leticia; McCully, Cynthia; Berg, Stacey L.; Blaney, Susan M.Clinical Cancer Research (2004), 10 (7), 2525-2529CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Imatinib mesylate (Gleevec, Glivec, STI571, imatinib) is a potent tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors. The role of imatinib in the treatment of malignant gliomas and other solid tumors is being evaluated. We used a nonhuman primate model that is highly predictive of the cerebrospinal fluid penetration of drugs in humans to study the pharmacokinetics of imatinib in plasma and cerebrospinal fluid (CSF) after i.v. and p.o. administration. Imatinib, 15 mg/kg i.v. over 30 min (n = 3) or 30 mg/kg p.o. (n = 3), was administered to nonhuman primates. Imatinib was measured in serial samples of plasma and CSF using high-pressure liq. chromatog. with UV absorbance or mass spectroscopic detection. Pharmacokinetic parameters were estd. using model-independent methods. Peak plasma imatinib concns. ranged from 6.4 to 9.5 μM after i.v. dosing and 0.8 to 2.8 μM after p.o. dosing. The mean ±SD area under the plasma concn. vs. time curve was 2480 ±1340 μM·min and 1191 ±146 μM·min after i.v. and p.o. dosing, resp. The terminal half-life was 529 ±167 min after i.v. dosing and 266 ±88 min after p.o. dosing. After i.v. dosing the steady state vol. of distribution was 5.9 ±2.8 L/kg, and the total body clearance was 12 ±5 mL/min/kg. The mean peak CSF concn. was 0.25 ±0.07 μM after i.v. dosing and 0.07 ±0.04 μM after p.o. dosing. The mean CSF:plasma area under the plasma concn. vs. time curve ratio for all of the animals was 5% ±2%. There is limited penetration of imatinib into the CSF of nonhuman primates after i.v. and p.o. administration.
- 262Das, J.; Chen, P.; Norris, D.; Padmanabha, R.; Lin, J.; Moquin, R. V.; Shen, Z.; Cook, L. S.; Doweyko, A. M.; Pitt, S.; Pang, S.; Shen, D. R.; Fang, Q.; de Fex, H. F.; McIntyre, K. W.; Shuster, D. J.; Gillooly, K. M.; Behnia, K.; Schieven, G. L.; Wityak, J.; Barrish, J. C. 2-Aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor J. Med. Chem. 2006, 49, 6819– 6832 DOI: 10.1021/jm060727j
- 263Remsing Rix, L. L.; Rix, U.; Colinge, J.; Hantschel, O.; Bennett, K. L.; Stranzl, T.; Müller, A.; Baumgartner, C.; Valent, P.; Augustin, M.; Till, J. H.; Superti-Funga, G. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells Leukemia 2009, 23, 477– 485 DOI: 10.1038/leu.2008.334[Crossref], [PubMed], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXivVKhu7w%253D&md5=b0d56d468ef66ddc2a6f012d08f8c1a4Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cellsRemsing Rix, L. L.; Rix, U.; Colinge, J.; Hantschel, O.; Bennett, K. L.; Stranzl, T.; Mueller, A.; Baumgartner, C.; Valent, P.; Augustin, M.; Till, J. H.; Superti-Furga, G.Leukemia (2009), 23 (3), 477-485CODEN: LEUKED; ISSN:0887-6924. (Nature Publishing Group)The detailed mol. mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chem. proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells vs. the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clin. important mutant to be enzymically inhibited in the mid-nanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation. Leukemia (2009) 23, 477-485; doi:10.1038/leu.2008.334; published online 27 Nov. 2008.
- 264(a) Du, J.; Bernasconi, P.; Clauser, K. R.; Mani, D. R.; Finn, S. P.; Beroukhim, R.; Burns, M.; Julian, B.; Peng, X. P.; Hieronymus, H.; Maglathin, R. L.; Lewis, T. A.; Liau, L. M.; Nghiemphu, P.; Mellinghoff, I. K.; Louis, D. N.; Loda, M.; Carr, S. A.; Kung, A. L.; Golub, T. R. Bead-based kinase phosphorylation profiling identifies SRC as a therapeutic target in glioblastoma Nat. Biotechnol. 2009, 27, 77– 83 DOI: 10.1038/nbt.1513(b) Zhang, S.; Huang, W.-C.; Zhang, L.; Zhang, C.; Lowery, F. J.; Ding, Z.; Guo, H.; Wang, H.; Huang, S.; Sahin, A. A.; Aldape, K. D.; Steeg, P. S.; Yu, D. Src family kinases as novel therapeutic targets to treat breast cancer brain metastases Cancer Res. 2013, 73, 5764– 5774 DOI: 10.1158/0008-5472.CAN-12-1803
- 265Chen, Y.; Agarwal, S.; Shaik, N. M.; Chen, C.; Yang, Z.; Elmquist, W. F. P-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinib J. Pharmacol. Exp. Ther. 2009, 330, 956– 963 DOI: 10.1124/jpet.109.154781[Crossref], [PubMed], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVyitL3F&md5=2b43bf0468e6fea3a5aae1f84b3fb69dP-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinibChen, Ying; Agarwal, Sagar; Shaik, Naveed M.; Chen, Cliff; Yang, Zheng; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2009), 330 (3), 956-963CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)The novel tyrosine kinase inhibitor dasatinib (Sprycel; BMS-354825) is approved for use in imatinib (Gleevec; STI 571)-resistant or -intolerant chronic myelogenous leukemia and may be useful for other tumors in the central nervous system (CNS). The objective of this study was to investigate the role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in modulating the CNS penetration of dasatinib. Results from the in vitro studies indicate that cellular delivery of dasatinib is significantly limited by active efflux due to both P-gp and BCRP. Permeability studies indicated greater permeability in the basolateral-to-apical direction than in the apical-to-basolateral direction due to active efflux by P-gp or BCRP. Selective inhibitors of P-gp and BCRP, such as (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo-(a,e)cyclopropa(c) cycloheptan-6-yl)-α-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride (zosuquidar; LY335979) and 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12α-octahydropyrazino1',2':1,6pryrido3,4-bindol-3-yl)-propionic acid tert-Bu ester (Ko143), were able to restore the intracellular accumulation and abolish the directionality in net flux of dasatinib. In vivo brain distribution studies showed that the CNS distribution of dasatinib is limited, with the brain-to-plasma concn. ratios less than 0.12 in wild-type mice, which increased approx. 8-fold in Mdr1a/b(-/-) Bcrp1(-/-) mice. Dasatinib brain distribution was significantly increased in Mdr1a/b(-/-) mice and when wild-type mice were pretreated with LY335979. Simultaneous inhibition of P-gp and BCRP by elacridar [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] (GF120918) resulted in a 5-fold increase in brain concn. These in vitro and in vivo studies demonstrate that dasatinib is a substrate for the important efflux transporters p-glycoprotein and BCRP. These transport systems play a significant role in limiting the CNS delivery of dasatinib and may have direct implications in the treatment of primary and metastatic brain tumors.
- 266Porkka, K.; Koskenvesa, P.; Lundan, T.; Rimpilainen, J.; Mustjoki, S.; Smykla, R.; Wild, R.; Luo, R.; Arnan, M.; Brethon, B.; Eccersley, L.; Hjorth-Hansen, H.; Hoglund, M.; Klamova, H.; Knutsen, H.; Parikh, S.; Raffoux, E.; Gruber, F.; Brito-Babapulle, F.; Dombret, H.; Duarte, R. F.; Elonen, E.; Paquette, R.; Zwaan, C. M.; Lee, F. Y. F. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia Blood 2008, 112, 1005– 1012 DOI: 10.1182/blood-2008-02-140665[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpvVOksL0%253D&md5=2edc2781403f7d921ec732db2e9cd560Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome-positive leukemiaPorkka, Kimmo; Koskenvesa, Perttu; Lundan, Tuija; Rimpilainen, Johanna; Mustjoki, Satu; Smykla, Richard; Wild, Robert; Luo, Roger; Arnan, Montserrat; Brethon, Benoit; Eccersley, Lydia; Hjorth-Hansen, Henrik; Hoglund, Martin; Klamova, Hana; Knutsen, Havar; Parikh, Suhag; Raffoux, Emmanuel; Gruber, Franz; Brito-Babapulle, Finella; Dombret, Herve; Duarte, Rafael F.; Elonen, Erkki; Paquette, Ron; Zwaan, C. Michel; Lee, Francis Y. F.Blood (2008), 112 (4), 1005-1012CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-pos. (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasatinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclin. mouse model of intracranial Ph+ leukemia. Clin. dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclin. studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasatinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clin. significant, long-lasting responses, which were complete in 7 patients. In 3 addnl. patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compd. in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clin. activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.
- 267Hegedus, C.; Özvegy-Laczka, C.; Apati, A.; Magocsi, M.; Nemet, K.; Orfi, L.; Keri, G.; Katona, M.; Takats, Z.; Varadi, A.; Szakacs, G.; Sarkadi, B. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties Br. J. Pharmacol. 2009, 158, 1153– 1164 DOI: 10.1111/j.1476-5381.2009.00383.x[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVSks7fM&md5=5f1105ff91e04f6f1b865591aeb0fcabInteraction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: Implications for altered anti-cancer effects and pharmacological propertiesHegedus, C.; Ozvegy-Laczka, C.; Apati, A.; Magocsi, M.; Nemet, K.; Orfi, L.; Keri, G.; Katona, M.; Takats, Z.; Varadi, A.; Szakacs, G.; Sarkadi, B.British Journal of Pharmacology (2009), 158 (4), 1153-1164CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)Background and purpose: ABC multidrug transporters (MDR-ABC proteins) cause multiple drug resistance in cancer and may be involved in the decreased anti-cancer efficiency and modified pharmacol. properties of novel specifically targeted agents. It has been documented that ABCB1 and ABCG2 interact with several first-generation, small-mol., tyrosine kinase inhibitors (TKIs), including the Bcr-Abl fusion kinase inhibitor imatinib, used for the treatment of chronic myeloid leukemia. Here, we have investigated the specific interaction of these transporters with nilotinib, dasatinib and bosutinib, three clin. used, second-generation inhibitors of the Bcr-Abl tyrosine kinase activity. Exptl. approach: MDR-ABC transporter function was screened in both membrane- and cell-based (K562 cells) systems. Cytotoxicity measurements in Bcr-Abl-pos. model cells were coupled with direct detn. of intracellular TKI concns. by high-pressure liq. chromatog.-mass spectrometry and anal. of the pattern of Bcr-Abl phosphorylation. Transporter function in membranes was assessed by ATPase activity. Key results: Nilotinib and dasatinib were high-affinity substrates of ABCG2, and this protein mediated an effective resistance in cancer cells against these compds. Nilotinib and dasatinib also interacted with ABCB1, but this transporter provided resistance only against dasatinib. Neither ABCB1 nor ABCG2 induced resistance to bosutinib. At relatively higher concns., however, each TKI inhibited both transporters. Conclusions and implications: A combination of in vitro assays may provide valuable preclin. information for the applicability of novel targeted anti-cancer TKIs, even in multidrug-resistant cancer. The pattern of MDR-ABC transporter-TKI interactions may also help to understand the general pharmacokinetics and toxicities of new TKIs.
- 268Atilla, E.; Ataca, P.; Ozyurek, E.; Erden, I.; Gurman, G. Successful bosutinib experience in an elderly acute lymphoblastic leukemia patient with suspected central nervous system involvement transformed from chronic myeloid leukemia Case Rep. Hematol. 2015, 2015, 689423 DOI: 10.1155/2015/689423[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28rkt1Squw%253D%253D&md5=55f21453f302c1d787e85e2951f18e5aSuccessful Bosutinib Experience in an Elderly Acute Lymphoblastic Leukemia Patient with Suspected Central Nervous System Involvement Transformed from Chronic Myeloid LeukemiaAtilla Erden; Ataca Pinar; Gurman Gunhan; Ozyurek Elif; Erden IlhanCase reports in hematology (2015), 2015 (), 689423 ISSN:2090-6560.Managing the blast phase in chronic myeloid leukemia (CML) is challenging because limited data are available for elderly patients. The involvement of the central nervous system (CNS) increases the risk of a poor prognosis. Here, we present an elderly blast phase CML patient with suspected CNS involvement who was successfully treated with bosutinib.
- 269Taylor, J. W.; Dietrich, J.; Gerstner, E. R.; Norden, A. D.; Rinne, M. L.; Cahill, D. P.; Stemmer-Rachamimov, A.; Wen, P. Y.; Betensky, R. A.; Giorgio, D. H.; Snodgrass, K.; Randall, A. E.; Batchelor, T. T.; Chi, A. S. Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma J. Neuro-Oncol. 2015, 121, 557– 563 DOI: 10.1007/s11060-014-1667-z[Crossref], [PubMed], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVWksLfJ&md5=6ad16c8f43cfd988185b43b7d5121656Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastomaTaylor, Jennie W.; Dietrich, Jorg; Gerstner, Elizabeth R.; Norden, Andrew D.; Rinne, Mikael L.; Cahill, Daniel P.; Stemmer-Rachamimov, Anat; Wen, Patrick Y.; Betensky, Rebecca A.; Giorgio, Diana H.; Snodgrass, Kellis; Randall, Alison E.; Batchelor, Tracy T.; Chi, Andrew S.Journal of Neuro-Oncology (2015), 121 (3), 557-563CODEN: JNODD2; ISSN:0167-594X. (Springer)Tumor cell infiltration is a major mechanism of treatment escape in glioblastoma. Src is an intracellular tyrosine kinase that mediates tumor cell motility and invasiveness. We evaluated the efficacy and safety of bosutinib, a tyrosine kinase inhibitor that potently inhibits Src and Abl, in patients with recurrent glioblastoma. In this two-arm study, patients with histol. confirmed recurrent glioblastoma and ≤2 relapses, not previously treated with anti-vascular endothelial growth factor (VEGF) therapy, were administered oral bosutinib 400 mg daily. Arm A planned for 6 patients who were candidates for surgical resection to be given bosutinib for 7-9 days prior to resection. Arm B was a two-stage design phase 2 trial targeting 30 patients. The primary endpoint was progression-free survival at 6 mo (PFS6) in Arm B. After 9 patients enrolled onto stage 1 of Arm B, 9 (100 %) patients progressed within 6 mo. Therefore, the study met the pre-specified criteria for early closure and both Arms were closed. In Arm B, Median PFS was 7.71 wk and median OS was 50 wk. Best objective response was stable disease in one patient (11.1 %). Seven patients (77.8 %) had treatment-related AEs of any grade and 2 (22.2 %) were grade ≥3. Arm A was closed after 2 patients enrolled. Src activation was evident in all archival tumor samples. Bosutinib monotherapy does not appear to be effective in recurrent glioblastoma. However, Src remains a potential target based on its upregulation in tumor samples and role in glioma invasion.
- 270(a) Kosztyu, P.; Dolezel, P.; Mlejnek, P. Can P-glycoprotein mediate resistance to nilotinib in human leukaemia cells? Pharmacol. Res. 2013, 67, 79– 83 DOI: 10.1016/j.phrs.2012.10.012[Crossref], [PubMed], [CAS], Google Scholar270ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVCktbzM&md5=2eb3d2796c8f45edaffb64a858a000b2Can P-glycoprotein mediate resistance to nilotinib in human leukaemia cells?Kosztyu, Petr; Dolezel, Petr; Mlejnek, PetrPharmacological Research (2013), 67 (1), 79-83CODEN: PHMREP; ISSN:1043-6618. (Elsevier Ltd.)The effect of P-glycoprotein (P-gp, ABCB1, MDR1) expression on cell resistance to nilotinib was studied in human leukemia cells. We used K562/Dox cells overexpressing P-gp and their variants (subclones) with a gradually decreased P-gp expression. These subclones were established by stable transfection of K562/Dox cells with a plasmid vector expressing shRNA targeting the ABCB1 gene. Functional anal. of P-gp using a specific fluorescent probe indicated gradually decreased dye efflux which was proportional to the P-gp expression. We obsd. that K562/Dox cells overexpressing P-gp contained a significantly reduced intracellular level of nilotinib when compared to their counter partner K562 cells, which do not express P-gp. This effect was accompanied by a decreased sensitivity of the K562/Dox cells to nilotinib. Importantly, cells with downregulated expression of P-gp gradually lost their ability to decrease the intracellular level of nilotinib although they still significantly decreased the intracellular level of daunorubicin (DNR). Accordingly, cells with the reduced expression of P-gp concomitantly failed to provide resistance to nilotinib, however, they exhibited a significant resistance to DNR. Taken together, we demonstrated that the conclusion as to whether P-gp is involved in nilotinib resistance or not strongly depends on its expression at protein level.(b) Yamakawa, Y.; Hamada, A.; Uchida, T.; Sato, D.; Yuki, M.; Hayashi, M.; Kawaguchi, T.; Saito, H. Distinct interaction of nilotinib and imatinib with P-glycoprotein in intracellular accumulation and cytotoxicity in CML cell line K562 cells Biol. Pharm. Bull. 2014, 37, 1330– 1335 DOI: 10.1248/bpb.b14-00254[Crossref], [PubMed], [CAS], Google Scholar270bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslWitbfK&md5=af5c25b1d5551f3e3c36d768d677f9c9Distinct interaction of nilotinib and imatinib with P-glycoprotein in intracellular accumulation and cytotoxicity in CML cell line K562 cellsYamakawa, Yuji; Hamada, Akinobu; Uchida, Takashi; Sato, Daisuke; Yuki, Misato; Hayashi, Masahiro; Kawaguchi, Tatsuya; Saito, HideyukiBiological & Pharmaceutical Bulletin (2014), 37 (8), 1330-1335CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for first-line chronic myeloid leukemia (CML) treatment. The improved clin. response of nilotinib over that of the first generation TKI, imatinib, has been thought to be a result of its high potency of inhibition of BCR-ABL kinase. This study aimed to characterize differences between nilotinib and imatinib in the intracellular accumulation and cytotoxic effect on the CML cell line K562. Accumulation of nilotinib in K562 cells was from 4.7- to 9.0-fold higher than that of imatinib. The cytotoxic effect of nilotinib on K562 cells was 14.2-fold higher than that of imatinib. Inhibition expts. in K562 cells, and examn. of the cellular uptake using influx transporter-transfected human embryonic kidney (HEK) 293 cells, suggested that the influx transporters OCT1 and OATP1A2, which have been reported to mediate accumulation of imatinib in CML cells, contributed little to the uptake of nilotinib. Nilotinib was found to accumulate in imatinib-resistant K562 (K562/IM) cells overexpressing the efflux transporter P-glycoprotein (P-gp), although cytotoxic assays showed that K562/IM cells displayed 20000-fold greater resistance to nilotinib over the parent K562 cells. In conclusion, the present findings suggest that intracellular accumulation of nilotinib in CML cells contributes to its clin. response and efficacy in CML patients. Although nilotinib has been reported to be effective against imatinib-resistant ABL kinase mutants, the drug could not overcome imatinib resistance acquired by P-gp-overexpression. These results imply that classification of mechanisms of drug resistance is important for suitable strategies to treat imatinib-resistant CML patients.
- 271Weisberg, E.; Manley, P. W.; Breitenstein, W.; Brüggen, J.; Cowan-jacob, S. W.; Ray, A.; Huntly, B.; Fabbro, D.; Fendrich, G.; Hall-Meyers, E.; Kung, A. L.; Mestan, J.; Daley, G. Q.; Callahan, L.; Catley, L.; Cavazza, C.; Mohammed, A.; Neuberg, D.; Wright, R. D.; Gilliand, D. G.; Griffin, J. D. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl Cancer Cell 2005, 7, 129– 141 DOI: 10.1016/j.ccr.2005.01.007[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXitFygu7o%253D&md5=d28e1a54b982951f8d3e6ef1d2d3b2ebCharacterization of AMN107, a selective inhibitor of native and mutant Bcr-AblWeisberg, Ellen; Manley, Paul W.; Breitenstein, Werner; Brueggen, Josef; Cowan-Jacob, Sandra W.; Ray, Arghya; Huntly, Brian; Fabbro, Doriano; Fendrich, Gabriele; Hall-Meyers, Elizabeth; Kung, Andrew L.; Mestan, Juergen; Daley, George Q.; Callahan, Linda; Catley, Laurie; Cavazza, Cara; Mohammed, Azam; Neuberg, Donna; Wright, Renee D.; Gilliland, D. Gary; Griffin, James D.Cancer Cell (2005), 7 (2), 129-141CODEN: CCAECI; ISSN:1535-6108. (Cell Press)The Bcr-Abl tyrosine kinase oncogene causes chronic myelogenous leukemia (CML) and Philadelphia chromosome-pos. (Ph+) acute lymphoblastic leukemia (ALL). We describe a novel selective inhibitor of Bcr-Abl, AMN107 (IC50 < 30 nM), which is significantly more potent than imatinib, and active against a no. of imatinib-resistant Bcr-Abl mutants. Crystallog. anal. of Abl-AMN107 complexes provides a structural explanation for the differential activity of AMN107 and imatinib against imatinib-resistant Bcr-Abl. Consistent with its in vitro and pharmacokinetic profile, AMN107 prolonged survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolonged survival in imatinib-resistant CML mouse models. AMN107 is a promising new inhibitor for the therapy of CML and Ph+ ALL.
- 272Reinwald, M.; Schleyer, E.; Kiewe, P.; Blau, I. W.; Burmeister, T.; Pursche, S.; Neumann, M.; Notter, M.; Thiel, E.; Hofmann, W.-K.; Kolb, H.-J.; Burdach, S.; Bender, H.-U. Efficacy and pharmacologic data of second-generation tyrosine kinase inhibitor nilotinib in BCR-ABL-positive leukemia patients with central nervous system relapse after allogeneic stem cell transplantation BioMed Res. Int. 2014, 2014, 637059 DOI: 10.1155/2014/637059
- 273Lonskaya, I.; Hebron, M. L.; Selby, S. T.; Turner, R. S.; Moussa, C. E.-H. Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in alzheimer’s disease models Neuroscience 2015, 304, 316– 327 DOI: 10.1016/j.neuroscience.2015.07.070
For example see the following and references therein:
[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1ygs7bO&md5=ada20cd34de6ec95abd50ff55426ba7cNilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer's disease modelsLonskaya, I.; Hebron, M. L.; Selby, S. T.; Turner, R. S.; Moussa, C. E.-H.Neuroscience (Amsterdam, Netherlands) (2015), 304 (), 316-327CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)Alzheimer's disease (AD) brains exhibit plaques and tangles in assocn. with inflammation. The non-receptor tyrosine kinase Abl is linked to neuro-inflammation in AD. Abl inhibition by nilotinib or bosutinib facilitates amyloid clearance and may decrease inflammation. Transgenic mice that express Dutch, Iowa and Swedish APP mutations (TgAPP) and display progressive Aβ plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to det. pre-plaque effects on systemic and CNS inflammation using milliplex ELISA. Plaque Aβ was detected at 4 mo in TgAPP and pre-plaque intracellular Aβ accumulation (2.5 mo) was assocd. with changes of cytokines and chemokines prior to detection of glial changes. Plaque formation correlated with increased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1α, IL-1β) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, Vascular Endothelial Growth Factor (VEGF) and IFN-γ. An inverse relationship of chemokines was obsd. as CCL2 and CCL5 were lower than WT mice at 2 mo and significantly increased after plaque appearance, while sol. CX3CL1 decreased. A change in glial profile was only robustly detected at 6 mo in Tg-APP mice and TKIs reduced astrocyte and dendritic cell no. with no effects on microglia, suggesting alteration of brain immunity. Nilotinib decreased blood and brain cytokines and chemokines and increased CX3CL1. Bosutinib increased brain and blood IL-10 and CX3CL1, suggesting a protective role for sol. CX3CL1. Taken together these data suggest that TKIs regulate systemic and CNS immunity and may be useful treatments in early AD through dual effects on amyloid clearance and immune modulation. - 274Huang, W.-S.; Metcalf, C. A.; Sundaramoorthi, R.; Wang, Y.; Zou, D.; Thomas, R. M.; Zhu, X.; Cai, L.; Wen, D.; Liu, S.; Romero, J.; Qi, J.; Chen, I.; Banda, G.; Lentini, S. P.; Das, S.; Xu, Q.; Keats, J.; Wang, F.; Wardwell, S.; Ning, Y.; Snodgrass, J. T.; Broudy, M. I.; Russian, K.; Zhou, T.; Commodore, L.; Narasimhan, N. I.; Mohemmad, Q. K.; Iuliucci, J.; Rivera, V. M.; Dalgarno, D. C.; Sawyer, T. K.; Clackson, T.; Shakespeare, W. C. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)-methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-Abelson (BCR-ABL) kinase including the T315I gatekeeper mutant J. Med. Chem. 2010, 53, 4701– 4719 DOI: 10.1021/jm100395q[ACS Full Text], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmslels7s%253D&md5=0dcd7b4ff31164b1d9883e897b7058ffDiscovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-[4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl]benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper MutantHuang, Wei-Sheng; Metcalf, Chester A.; Sundaramoorthi, Raji; Wang, Yihan; Zou, Dong; Thomas, R. Mathew; Zhu, Xiaotian; Cai, Lisi; Wen, David; Liu, Shuangying; Romero, Jan; Qi, Jiwei; Chen, Ingrid; Banda, Geetha; Lentini, Scott P.; Das, Sasmita; Xu, Qihong; Keats, Jeff; Wang, Frank; Wardwell, Scott; Ning, Yaoyu; Snodgrass, Joseph T.; Broudy, Marc I.; Russian, Karin; Zhou, Tianjun; Commodore, Lois; Narasimhan, Narayana I.; Mohemmad, Qurish K.; Iuliucci, John; Rivera, Victor M.; Dalgarno, David C.; Sawyer, Tomi K.; Clackson, Tim; Shakespeare, William C.Journal of Medicinal Chemistry (2010), 53 (12), 4701-4719CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate benzamide I (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC50s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of I significantly prolonged survival of mice injected i.v. with BCR-ABLT315I expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of I to be an effective treatment for CML, including patients refractory to all currently approved therapies.
- 275Laramy, J. K.; Parrish, K. E.; Zhang, S.; Bakken, K. K.; Carlson, B. L.; Mladek, A. C.; Ma, D. J.; Sarkaria, J. N.; Elmquist, W. F. Brain distribution of ponatinib, a multi-kinase inhibitor: implications for the treatment of malignant brain tumors Am. Assoc. Pharm. Sci. 2015, W4339
- 276Niwa, T.; Asaki, T.; Kimura, S. NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor Anal. Chem. Insights 2007, 2, 93– 106[Crossref], [PubMed], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MrktFSnsA%253D%253D&md5=5c846df1ba45ec0d09d3a0d2cb8ee20eNS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitorNiwa Tomoko; Asaki Tetsuo; Kimura ShinyaAnalytical chemistry insights (2007), 2 (), 93-106 ISSN:.Protein kinases catalyze the transfer of the gamma-phosphoryl group of adenosine triphosphate (ATP) to the hydroxyl groups of protein side chains, and they play critical roles in regulating cellular signal transduction and other biochemical processes. They are attractive targets for today's drug discovery and development, and many pharmaceutical companies are intensively developing various kinds of protein kinase inhibitors. A good example is the recent success with the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (Gleevec) in the treatment of chronic myeloid leukemia. Though imatinib has dramatically improved the treatment of Bcr-Abl-positive chronic myeloid leukemia, resistance is often found in patients with advanced-stage disease. Several mechanisms have been proposed to explain this resistance, including point mutations within the Abl kinase domain, amplification of the bcr-abl gene, overexpression of the corresponding mRNA, increased drug efflux mediated by P-glycoprotein, and activation of the Src-family kinase (SFK) Lyn. We set out to develop a novel drug whose affinity for Abl is higher than that of imatinib and whose specificity in inhibiting Lyn is higher than that of SFK/Abl inhibitors such as dasatinib (Sprycel) or bosutinib (SKI-606). Our work has led to the development of NS-187 (INNO-406), a novel Abl/Lyn dual tyrosine kinase inhibitor with clinical prospects. To provide an overview of how a selective kinase inhibitor has been developed, this review presents chemical-modification studies carried out with the guidance of molecular modeling, the structural basis for the high potency and selectivity of NS-187 based on the X-ray structure of the NS-187/Abl complex, and the biological profiling of NS-187, including site-directed mutagenesis experiments.
- 277Portnow, J.; Badie, B.; Markel, S.; Liu, A.; D’Apuzzo, M.; Frankel, P.; Jandial, R.; Synold, T. W. A neuropharmocokinetic assessment of bafetinib, a second generation dual BCR-Abl/Lyn tyrosine kinase inhibitor, in patients with recurrent high-grade gliomas Eur. J. Cancer 2013, 49, 1634– 1640 DOI: 10.1016/j.ejca.2013.01.001
- 278Yokota, A.; Kimura, S.; Masuda, S.; Ashihara, E.; Kuroda, J.; Sato, K.; Kamitsuji, Y.; Kawata, E.; Deguchi, Y.; Urasaki, Y.; Terui, Y.; Ruthardt, M.; Ueda, T.; Hatake, K.; Inui, K.; Maekawa, T. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity Blood 2007, 109, 306– 314 DOI: 10.1182/blood-2006-03-013250
- 279Hennequin, L. F.; Allen, J.; Breed, J.; Curwen, J.; Fennell, M.; Green, T. P.; Lambert-van der Brempt, C.; Morgentin, R.; Norman, R. A.; Olivier, A.; Otterbein, L.; Ple, P. A.; Warin, N.; Costello, G. N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor J. Med. Chem. 2006, 49, 6465– 6488 DOI: 10.1021/jm060434q
- 280Kaufman, A. C.; Salazar, S. V.; Haas, L. T.; Yang, J.; Kostylev, M. A.; Jeng, A. T.; Robinson, S. A.; Gunther, E. C.; van Dyck, C. H.; Nygaard, H. B.; Strittmatter, S. M. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice Ann. Neurol. 2015, 77, 953– 971 DOI: 10.1002/ana.24394[Crossref], [PubMed], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpt1yitro%253D&md5=dbefcbdecd53b505110110f41e6174bdFyn inhibition rescues established memory and synapse loss in Alzheimer miceKaufman, Adam C.; Salazar, Santiago V.; Haas, Laura T.; Yang, Jinhee; Kostylev, Mikhail A.; Jeng, Amanda T.; Robinson, Sophie A.; Gunther, Erik C.; van Dyck, Christopher H.; Nygaard, Haakon B.; Strittmatter, Stephen M.Annals of Neurology (2015), 77 (6), 953-971CODEN: ANNED3; ISSN:0364-5134. (John Wiley & Sons, Inc.)Objective: Currently no effective disease-modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathol. triggered by amyloid-β oligomers (Aβo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncol. compd., AZD0530, for AD. Methods: The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aβo signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild-type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metab., synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochem. and by immunoblotting. Results : AZD0530 potently inhibits Fyn and prevents both Asso-induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 wk of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Ass metab. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. Interpretation: Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse d. loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD.
- 281Nygaard, H. B.; Wagner, A. F.; Bowen, G. S.; Good, S. P.; MacAvoy, M. G.; Strittmatter, K. A.; Kaufman, A. C.; Rosenberg, B. J.; Sekine-Konno, T.; Varma, P.; Chen, K.; Koleske, A. J.; Reiman, E. M.; Strittmatter, S. M.; van Dyck, C. H. A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer’s disease Alzheimer's Res. Ther. 2015, 7, 35 DOI: 10.1186/s13195-015-0119-0[Crossref], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MjktlSjtA%253D%253D&md5=fda8573af23de7ef7468acbfd5879094A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's diseaseNygaard Haakon B; Wagner Allison F; Bowen Garrett S; Good Susan P; MacAvoy Martha G; Strittmatter Kurt A; Kaufman Adam C; Rosenberg Brian J; Sekine-Konno Tomoko; Varma Pradeep; Chen Kewei; Reiman Eric M; Koleske Anthony J; Strittmatter Stephen M; van Dyck Christopher HAlzheimer's research & therapy (2015), 7 (1), 35 ISSN:.INTRODUCTION: Despite significant progress, a disease-modifying therapy for Alzheimer's disease (AD) has not yet been developed. Recent findings implicate soluble oligomeric amyloid beta as the most relevant protein conformation in AD pathogenesis. We recently described a signaling cascade whereby oligomeric amyloid beta binds to cellular prion protein on the neuronal cell surface, activating intracellular Fyn kinase to mediate synaptotoxicity. Fyn kinase has been implicated in AD pathophysiology both in in vitro models and in human subjects, and is a promising new therapeutic target for AD. Herein, we present a Phase Ib trial of the repurposed investigational drug AZD0530, a Src family kinase inhibitor specific for Fyn and Src kinase, for the treatment of patients with mild-to-moderate AD. METHODS: The study was a 4-week Phase Ib multiple ascending dose, randomized, double-blind, placebo-controlled trial of AZD0530 in AD patients with Mini-Mental State Examination (MMSE) scores ranging from 16 to 26. A total of 24 subjects were recruited in three sequential groups, with each randomized to receive oral AZD0530 at doses of 50 mg, 100 mg, 125 mg, or placebo daily for 4 weeks. The drug:placebo ratio was 3:1. Primary endpoints were safety, tolerability, and cerebrospinal fluid (CSF) penetration of AZD0530. Secondary endpoints included changes in clinical efficacy measures (Alzheimer's Disease Assessment Scale - cognitive subscale, MMSE, Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory, Neuropsychiatric Inventory, and Clinical Dementia Rating Scale - Sum of Boxes) and regional cerebral glucose metabolism measured by fluorodeoxyglucose positron emission tomography. RESULTS: AZD0530 was generally safe and well tolerated across doses. One subject receiving 125 mg of AZD0530 was discontinued from the study due to the development of congestive heart failure and atypical pneumonia, which were considered possibly related to the study drug. Plasma/CSF ratio of AZD0530 was 0.4. The 100 mg and 125 mg doses achieved CSF drug levels corresponding to brain levels that rescued memory deficits in transgenic mouse models. One-month treatment with AZD0530 had no significant effect on clinical efficacy measures or regional cerebral glucose metabolism. CONCLUSIONS: AZD0530 is reasonably safe and well tolerated in patients with mild-to-moderate AD, achieving substantial central nervous system penetration with oral dosing at 100-125 mg. Targeting Fyn kinase may be a promising therapeutic approach in AD, and a larger Phase IIa clinical trial of AZD0530 for the treatment of patients with AD has recently launched. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01864655. Registered 12 June 2014.
- 282(a) Abounader, R.; Laterra, J. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis Neuro-Oncology 2005, 7, 436– 451 DOI: 10.1215/S1152851705000050(b) Zhang, Y.; Farenholtz, K. E.; Yang, Y.; Guessous, F.; diPierro, C. G.; Calvert, V. S.; Deng, J.; Schiff, D.; Xin, W.; Lee, J. K.; Purow, B.; Christensen, J.; Petricoin, E.; Abounader, R. Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition Clin. Cancer Res. 2013, 19, 1433– 1444 DOI: 10.1158/1078-0432.CCR-12-2832[Crossref], [PubMed], [CAS], Google Scholar282bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktFKktro%253D&md5=182ec75be957278f9f46eb2013f702fcHepatocyte Growth Factor Sensitizes Brain Tumors to c-MET Kinase InhibitionZhang, Ying; Farenholtz, Kaitlyn E.; Yang, Yanzhi; Guessous, Fadila; diPierro, Charles G.; Calvert, Valerie S.; Deng, Jianghong; Schiff, David; Xin, Wenjun; Lee, Jae K.; Purow, Benjamin; Christensen, James; Petricoin, Emanuel; Abounader, RogerClinical Cancer Research (2013), 19 (6), 1433-1444CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clin. applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not-well-known mol. determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors. Exptl. Design: We investigated the mol. factors and pathway activation signatures that det. sensitivity to c-MET inhibitors in a panel of glioblastoma and medulloblastoma cells, glioblastoma stem cells, and established cell line-derived xenografts using functional assays, reverse protein microarrays, and in vivo tumor vol. measurements, but validation with animal survival analyses remains to be done. We also explored new approaches for improving the efficacy of the inhibitors in vitro and in vivo. Results: We found that HGF coexpression is a key predictor of response to c-MET inhibition among the examd. factors and identified an ERK/JAK/p53 pathway activation signature that differentiates c-MET inhibition in responsive and nonresponsive cells. Surprisingly, we also found that short pretreatment of cells and tumors with exogenous HGF moderately but statistically significantly enhanced the antitumor effects of c-MET inhibition. We obsd. a similar ligand-induced sensitization effect to an EGF receptor small-mol. kinase inhibitor. Conclusions: These findings allow the identification of a subset of patients that will be responsive to c-MET inhibition and propose ligand pretreatment as a potential new strategy for improving the anticancer efficacy of RTK inhibitors. Clin Cancer Res; 19(6); 1433-44. ©2013 AACR.
- 283Qian, F.; Engst, S.; Yamaguchi, K.; Yu, P.; Won, K. A.; Mock, L.; Lou, T.; Tan, J.; Li, C.; Tam, D.; Lougheed, J.; Yakes, F. M.; Bentzien, F.; Xu, W.; Zaks, T.; Wooster, R.; Greshock, J.; Joly, A. H. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases Cancer Res. 2009, 69, 8009– 8016 DOI: 10.1158/0008-5472.CAN-08-4889[Crossref], [PubMed], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1ynurbF&md5=f3bf5b432ee42b164d23b690828e3c78Inhibition of Tumor Cell Growth, Invasion, and Metastasis by EXEL-2880 (XL880, GSK1363089), a Novel Inhibitor of HGF and VEGF Receptor Tyrosine KinasesQian, Fawn; Engst, Stefan; Yamaguchi, Kyoko; Yu, Peiwen; Won, Kwang-Ai; Mock, Lillian; Lou, Tracy; Tan, Jenny; Li, Connie; Tam, Danny; Lougheed, Julie; Yakes, F. Michael; Bentzien, Frauke; Xu, Wei; Zaks, Tal; Wooster, Richard; Greshock, Joel; Joly, Alison H.Cancer Research (2009), 69 (20), 8009-8016CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a wide variety of human malignancies. Vascular endothelial growth factor (VEGF) receptors are expressed on the surface of vascular endothelial cells and cooperate with Met to induce tumor invasion and vascularization. EXEL-2880 (XL880, GSK1363089) is a small-mol. kinase inhibitor that targets members of the HGF and VEGF receptor tyrosine kinase families, with addnl. inhibitory activity toward KIT, Flt-3, platelet-derived growth factor receptor β, and Tie-2. Binding of EXEL-2880 to Met and VEGF receptor 2 (KDR) is characterized by a very slow off-rate, consistent with X-ray crystallog. data showing that the inhibitor is deeply bound in the Met kinase active site cleft. EXEL-2880 inhibits cellular HGF-induced Met phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and prevents both HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells. In addn., EXEL-2880 prevents anchorage-independent proliferation of tumor cells under both normoxic and hypoxic conditions. In vivo, these effects produce significant dose-dependent inhibition of tumor burden in an exptl. model of lung metastasis. Collectively, these data indicate that EXEL-2880 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion and angiogenesis mediated by HGF and VEGF receptors.
- 284Faria, C. C.; Golbourn, B. J.; Dubuc, A. M.; Remke, M.; Diaz, R. J.; Agnihotri, S.; Luck, A.; Sabha, N.; Olsen, S.; Wu, X.; Garzia, L.; Ramaswamy, V.; Mack, S. C.; Wang, X.; Leadley, M.; Reynaud, D.; Ermini, L.; Post, M.; Northcott, P. A.; Pfister, S. M.; Croul, S. E.; Kool, M.; Korshunov, A.; Smith, C. A.; Taylor, M. D.; Rutka, J. T. Foretinib is effective for metastatic sonic hedgehog medulloblastoma Cancer Res. 2015, 75, 134– 146 DOI: 10.1158/0008-5472.CAN-13-3629
- 285Buchanan, S. G.; Hendle, J.; Lee, P. S.; Smith, C. R.; Bounaud, P. Y.; Jessen, K. A.; Tang, C. M.; Huser, N. H.; Felce, J. D.; Froning, K. J.; Peterman, M. C.; Aubol, B. E.; Gessert, S. F.; Sauder, J. M.; Schwinn, K. D.; Russell, M.; Rooney, I. A.; Adams, J.; Leon, B. C.; Do, T. H.; Blaney, J. M.; Sprengeler, P. A.; Thompson, D. A.; Smyth, L.; Pelletier, L. A.; Atwell, S.; Holme, K.; Wasserman, S. R.; Emtage, S.; Burley, S. K.; Reich, S. H. SGX is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo Mol. Cancer Ther. 2009, 8, 3181– 3190 DOI: 10.1158/1535-7163.MCT-09-0477[Crossref], [PubMed], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFCitbzI&md5=7410ae811f0bf2d3298691ed34d35878SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivoBuchanan, Sean G.; Hendle, Jorg; Lee, Patrick S.; Smith, Christopher R.; Bounaud, Pierre-Yves; Jessen, Katti A.; Tang, Crystal M.; Huser, Nanni H.; Felce, Jeremy D.; Froning, Karen J.; Peterman, Marshall C.; Aubol, Brandon E.; Gessert, Steve F.; Sauder, J. Michael; Schwinn, Kenneth D.; Russell, Marijane; Rooney, Isabelle A.; Adams, Jason; Leon, Barbara C.; Do, Tuan H.; Blaney, Jeff M.; Sprengeler, Paul A.; Thompson, Devon A.; Smyth, Lydia; Pelletier, Laura A.; Atwell, Shane; Holme, Kevin; Wasserman, Stephen R.; Emtage, Spencer; Burley, Stephen K.; Reich, Siegfried H.Molecular Cancer Therapeutics (2009), 8 (12), 3181-3190CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)The MET receptor tyrosine kinase has emerged as an important target for the development of novel cancer therapeutics. Activation of MET by mutation or gene amplification has been linked to kidney, gastric, and lung cancers. In other cancers, such as glioblastoma, autocrine activation of MET has been demonstrated. Several classes of ATP-competitive inhibitor have been described, which inhibit MET but also other kinases. Here, we describe SGX523, a novel, ATP-competitive kinase inhibitor remarkable for its exquisite selectivity for MET. SGX523 potently inhibited MET with an IC50 of 4 nmol/L and is >1000-fold selective vs. the >200-fold selectivity of other protein kinases tested in biochem. assays. Crystallog. study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity. SGX523 inhibited MET-mediated signaling, cell proliferation, and cell migration at nanomolar concns. but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concns. SGX523 inhibition of MET in vivo was assocd. with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. Our results show that SGX523 is the most selective inhibitor of MET catalytic activity described to date and is thus a useful tool to investigate the role of MET kinase in cancer without the confounding effects of promiscuous protein kinase inhibition.
- 286Guessous, F.; Zhang, Y.; diPierro, C.; Marcinkiewicz, L.; Sarkaria, J.; Schiff, D.; Buchanan, S.; Abounader, R. An orally bioavailable c-Met kinase inhibitor potently inhibits brain tumor malignancy and growth Anti-Cancer Agents Med. Chem. 2010, 10, 28– 35 DOI: 10.2174/1871520611009010028
- 287(a) Underiner, T. L.; Herbertz, T.; Miknyoczki, S. J. Disovery of small molecule c-Met inhibitors: evolution and profiles of clinical candidates Anti-Cancer Agents Med. Chem. 2010, 10, 7– 27 DOI: 10.2174/1871520611009010007(b) Burbridge, M. F.; Bossard, C. J.; Saunier, C.; Fejes, I.; Bruno, I.; Bruno, A.; Leonce, S.; Ferry, G.; Da Violante, G.; Bouzom, F.; Cattan, V.; Jacquet-Bescond, A.; Comoglio, P. M.; Lockhart, B. P.; Boutin, J. A.; Cordi, A.; Ortuno, J. C.; Pierre, A.; Hickman, J. A.; Cruzalegui, F. H.; Depil, S. S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab Mol. Cancer Ther. 2013, 12, 1749– 1762 DOI: 10.1158/1535-7163.MCT-13-0075[Crossref], [PubMed], [CAS], Google Scholar287bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtl2lur7O&md5=a53009f7a7b0601cf45598ca5b8775c2S49076 Is a Novel Kinase Inhibitor of MET, AXL, and FGFR with Strong Preclinical Activity Alone and in Association with BevacizumabBurbridge, Mike F.; Bossard, Celine J.; Saunier, Carine; Fejes, Imre; Bruno, Alain; Leonce, Stephane; Ferry, Gilles; Da Violante, Georges; Bouzom, Francois; Cattan, Valerie; Jacquet-Bescond, Anne; Comoglio, Paolo M.; Lockhart, Brian P.; Boutin, Jean A.; Cordi, Alex; Ortuno, Jean-Claude; Pierre, Alain; Hickman, John A.; Cruzalegui, Francisco H.; Depil, StephaneMolecular Cancer Therapeutics (2013), 12 (9), 1749-1762CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been assocd. with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclin. characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclin. studies showing a favorable and novel pharmacol. profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749-62. ©2013 AACR.
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Literature related to the following c-Met inhibitors was reviewed in an effort to identify any information regarding potential for CNS penetration, including whether the molecules are P-gp substrates: LY2801653, PF-04217903, golvatinib, JNJ-58877605, PHA-66752, tivantinib.
There is no corresponding record for this reference. - 289(a) Gutenberg, A.; Brück, W.; Buchfelder, M.; Ludwig, H. C. Expression of tyrosine kinases FAK and Pyk2 in 331 human astrocytomas Acta Neuropathol. 2004, 108, 224– 230 DOI: 10.1007/s00401-004-0886-3[Crossref], [PubMed], [CAS], Google Scholar289ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmt1Krur8%253D&md5=05f4ecbba6b2aabbef6fd97445398d27Expression of tyrosine kinases FAK and Pyk2 in 331 human astrocytomasGutenberg, A.; Brueck, W.; Buchfelder, M.; Ludwig, H. C.Acta Neuropathologica (2004), 108 (3), 224-230CODEN: ANPTAL; ISSN:0001-6322. (Springer GmbH)The progression of malignancy from astrocytomas to glioblastomas remains clin. as well as histopathol. unpredictable. The focal adhesion kinase (FAK) and the proline-rich Tyr kinase (Pyk2) show a high expression in glioma cell lines and have an influence on increased cell proliferation and migration of glioma cells in vitro and in vivo. The aim of this study was to correlate the coexpression of FAK and Pyk2 to the WHO grade of malignancy in human astrocytomas. Immunohistochem. staining scores of FAK and Pyk2 were analyzed in 331 astrocytomas and correlated to each other and to the WHO grade. Significant coexpression of FAK and Pyk2 in astrocytomas was demonstrated. Pyk2 expression occurred much more frequently and with higher expression scores within the different WHO grades. Beyond this, a significant correlation between the WHO grade of malignancy of astrocytomas and the expression of FAK, as well as of Pyk2, was detected. This connection and the roles of these 2 Tyr kinases in the progression of tumors should be confirmed by further studies.(b) Rolon-Reyes, K.; Kucheryavykh, Y. V.; Cubano, L. A.; Inyushin, M.; Skatchkov, S. N.; Eaton, M. J.; Harrison, J. K.; Kucheryavykh, L. Y. Microglia activate migration of glioma cells through a Pyk2 intracellular pathway PLoS One 2015, 10, e0131059 DOI: 10.1371/journal.pone.0131059
- 290Sulzmaier, F. J.; Jean, C.; Schlaepfer, D. D. FAK in cancer: mechanistic findings and clinical applications Nat. Rev. Cancer 2014, 14, 598– 610 DOI: 10.1038/nrc3792[Crossref], [PubMed], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht12nu7vJ&md5=f498bcf7af890d2f92eda68e42f979d1FAK in cancer: mechanistic findings and clinical applicationsSulzmaier, Florian J.; Jean, Christine; Schlaepfer, David D.Nature Reviews Cancer (2014), 14 (9), 598-610CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. FAK promotes tumor progression and metastasis through effects on cancer cells, as well as stromal cells of the tumor microenvironment. The kinase-dependent and kinase-independent functions of FAK control cell movement, invasion, survival, gene expression and cancer stem cell self-renewal. Small mol. FAK inhibitors decrease tumor growth and metastasis in several preclin. models and have initial clin. activity in patients with limited adverse events. In this Review, we discuss FAK signalling effects on both tumor and stromal cell biol. that provide rationale and support for future therapeutic opportunities.
- 291Luzzio, M.; Autry, C.; Berliner, M.; Coleman, K.; Cooper, B.; Desrosiers, E.; Emerson, E.; Griffor, M.; Hulford, C.; Jani, J.; Kath, J.; LaGreca, S.; Lin, J.; Lorenzen, M.; Marr, E.; Martinez-Alsina, L.; Patel, N.; Richter, D.; Ung, E.; Vajdos, F.; Wessel, M.; Whalen, P.; Yao, L.; Roberts, W. Abstract 5432: Design, synthesis, activity and properties of selective focal adhesion kinase inhibitors which are suitable for advanced preclinical evaluation: the discovery of PF-562271 Cancer Res. 2007, 67 (Suppl.) 5432
- 292Xu, Q.; Pachter, J. A.; Tam, W. Methods and compositions for treating abnormal cell growth (e.g., cancer) using FAK inhibitor and a MEK inhibitor. WO Patent WO2015120289 A1, 2015.
- 293Schlaepfer, D. Method of promoting apoptosis and inhibiting metastasis. WO Patent WO2011019943 A1, 2011.
- 294Auger, K. R.; Peddareddigari, V. G. R. Combinations. WO Patent WO2014059095 A1, 2014.
- 295Mulholland, P.; Williams, M.; Arkenau, H. T.; Fleming, R.; Tolson, J.; Yan, L.; Zhang, J.; Swartz, L.; Singh, R.; Auger, K.; Lenox, L.; Cox, D.; Plisson, C.; Saleem, A.; Searle, G.; Blagden, S. ATNT 06. Evaluation of the safety of GSK2256098 and pharmacokinetics of 11C-GSK2256098 in patients with recurrent glioblastoma by positron emission tomography (PET) imaging Neuro-Oncology 2015, 17 (Suppl. 5) v11 DOI: 10.1093/neuonc/nov205.06
- 296(a) Han, J.; Alvarez-Breckenridge, C. A.; Wang, Q. E.; Yu, J. TGF-b signaling and its targeting for glioma treatment Am. J. Cancer Res. 2015, 5, 945– 955[PubMed], [CAS], Google Scholar296ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MbgslCisw%253D%253D&md5=6722803b2cc34a4e7343f91c0da9664cTGF-β signaling and its targeting for glioma treatmentHan Jianfeng; Yu Jianhua; Alvarez-Breckenridge Christopher A; Wang Qi-EnAmerican journal of cancer research (2015), 5 (3), 945-55 ISSN:.Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine, secreted by a variety of cells including immune cells, tumor cells, and stromal cells. TGF-β signaling is dysregulated in cancer patients, and this aberrant signaling at least in part contributes to initiation and progression of many cancers including glioma. The dysregulated signaling components provide molecular targets for the treatment of glioma. In this article, we review TGF-β signaling and its targeting in glioma.(b) Luwor, R. B.; Kaye, A. H.; Zhu, H. J. Transforming growth factor-beta (TGF-b) and brain tumors J. Clin. Neurosci. 2008, 15, 845– 855 DOI: 10.1016/j.jocn.2008.01.003[Crossref], [PubMed], [CAS], Google Scholar296bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnvVOntrw%253D&md5=1e135fed7c8de3aa3a0d4f8ec24b39f5Transforming growth factor-beta (TGF-β) and brain tumoursLuwor, Rodney B.; Kaye, Andrew H.; Zhu, Hong-JianJournal of Clinical Neuroscience (2008), 15 (8), 845-855CODEN: JCNUE6; ISSN:0967-5868. (Elsevier B.V.)A review. Since its discovery in the late 1970s considerable research has linked transforming growth factor-beta (TGF-β) to several human diseases such as fibrosis, auto-immunity and cancer. TGF-β acts initially as a growth inhibitory factor in early stages of tumor development. In contrast, as tumors evolve, they develop mechanisms to evade the growth-regulatory effects of TGF-β, resulting in greater tumor invasiveness, increased metastatic potential and inhibition of surrounding immune responses. However, although extensively studied, the mol. mechanisms that trigger tumor cells to "switch" from TGF-β-inhibited to TGF-β-promoted are still not fully understood. Contradictory studies that demonstrate opposite cellular effects mediated by TGF-β are abundant throughout the literature. This review summarizes the current mol. mechanisms involved in the tumor suppressive and tumor progressive characteristics of TGF-β in brain tumors. Potential therapeutic agents that target TGF-β and related proteins being evaluated against brain tumors is also discussed.
- 297Herbertz, S.; Sawyer, J. S.; Stauber, A. J.; Gueorguieva, I.; Driscoll, K. E.; Estrem, S. T.; Cleverly, A. L.; Desaiah, D.; Guba, S. C.; Benhadji, K. A.; Slapak, C. A.; Lahn, M. M. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta singaling pathway Drug Des., Dev. Ther. 2015, 9, 4479– 4499 DOI: 10.2147/DDDT.S86621[Crossref], [PubMed], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC287nsVChuw%253D%253D&md5=37fa07dc9996dc98fafdab1a658f0d96Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathwayHerbertz Stephan; Sawyer J Scott; Stauber Anja J; Estrem Shawn T; Desaiah Durisala; Guba Susan C; Benhadji Karim A; Slapak Christopher A; Lahn Michael M; Gueorguieva Ivelina; Cleverly Ann L; Driscoll Kyla EDrug design, development and therapy (2015), 9 (), 4479-99 ISSN:.Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.
- 298Herzog, S.; Fink, M. A.; Weitmann, K.; Friedel, C.; Hadlich, S.; Langner, S.; Kindermann, K.; Holm, T.; Bohm, A.; Eskilsson, E.; Miletic, H.; Hildner, M.; Fritsch, M.; Vogelgesang, S.; Havemann, C.; Ritter, C. A.; Meyer zu Schwabedissen, H. E.; Rauch, B.; Hoffmann, W.; Kroemer, H. K.; Schroeder, H.; Bien-Moller, S. Pim1 kinase is upregulated in glioblastoma multiforme and mediates tumor cell survival Neuro-Oncology 2015, 17, 223– 242 DOI: 10.1093/neuonc/nou216
- 299Chen, L. S.; Redkar, S.; Bearss, D.; Wierda, W. G.; Gandhi, V. Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells Blood 2009, 114, 4150– 4157 DOI: 10.1182/blood-2009-03-212852[Crossref], [PubMed], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVGku7vL&md5=3ef35f4c41c753a9c1c8245a6392bce2Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cellsChen, Lisa S.; Redkar, Sanjeev; Bearss, David; Wierda, William G.; Gandhi, VarshaBlood (2009), 114 (19), 4150-4157CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)Pim kinases are involved in B-cell development and are overexpressed in B-cell chronic lymphocytic leukemia (CLL). We hypothesized that Pim kinase inhibition would affect B-cell survival. Identified from a screen of imidazo[1,2-b]pyridazine compds., SGI-1776 inhibits Pim-1, Pim-2, and Pim-3. Treatment of CLL cells with SGI-1776 results in a concn.-dependent induction of apoptosis. To elucidate its mechanism of action, we evaluated the effect of SGI-1776 on Pim kinase function. Unlike in replicating cells, phosphorylation of traditional Pim-1 kinase targets, phospho-Bad (Ser112) and histone H3 (Ser10), and cell-cycle proteins were unaffected by SGI-1776, suggesting an alternative mechanism in CLL. Protein levels of total c-Myc as well as phospho-c-Myc(Ser62), a Pim-1 target site, were decreased after SGI-1776 treatment. Levels of antiapoptotic proteins Bcl-2, Bcl-XL, XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant redn. in Mcl-1 was obsd. that was not caused by caspase-mediated cleavage of Mcl-1 protein. The mechanism of decline in Mcl-1 was at the RNA level and was correlated with inhibition of global RNA synthesis. Consistent with a decline in new RNA synthesis, MCL-1 transcript levels were decreased after treatment with SGI-1776. These data suggest that SGI-1776 induces apoptosis in CLL and that the mechanism involves Mcl-1 redn.
- 300Burger, M. T.; Nishiguchi, G.; Han, W.; Lan, J.; Simmons, R.; Atallah, G.; Ding, Y.; Tamez, V.; Zhang, Y.; Mathur, M.; Muller, K.; Bellamacina, C.; Lindvall, M. K.; Zang, R.; Huh, K.; Feucht, P.; Zavorotinskaya, T.; Dai, Y.; Basham, S.; Chan, J.; Ginn, E.; Aycinena, A.; Holash, J.; Castillo, J.; Langowski, J. L.; Wang, Y.; Chen, M. Y.; Lambert, A.; Fritsch, C.; Kauffmann, A.; Pfister, E.; Vanasse, K. G.; Garcia, P. D. Identification of N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a potent and selective proviral insertion site of moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitor in clinical trials for hematological malignancies J. Med. Chem. 2015, 58, 8373– 8386 DOI: 10.1021/acs.jmedchem.5b01275
- 301Keeton, E. K.; McEachern, K.; Dillman, K. S.; Palakurthi, S.; Cao, Y.; Grondine, M. R.; Kaur, S.; Wang, S.; Chen, Y.; Wu, A.; Shen, M.; Gibbons, F. D.; Lamb, M. L.; Zheng, X.; Stone, R. M.; DeAngelo, D. J.; Platanias, L. C.; Dakin, L. A.; Chen, H.; Lyne, P. D.; Huszar, D. AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia Blood 2014, 123, 905– 913 DOI: 10.1182/blood-2013-04-495366[Crossref], [PubMed], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisFaqs7o%253D&md5=4277790b53c9064787cbd68c159e552bAZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemiaKeeton, Erika K.; McEachern, Kristen; Dillman, Keith S.; Palakurthi, Sangeetha; Cao, Yichen; Grondine, Michael R.; Kaur, Surinder; Wang, Suping; Chen, Yuching; Wu, Allan; Shen, Minhui; Gibbson, Francis D.; Lamb, Michelle L.; Zheng, Xiaolan; Stone, Richard M.; DeAngelo, Daniel J.; Platanias, Leonidas C.; Dakin, Les A.; Chen, Huawei; Lyne, Paul D.; Huszar, DennisBlood (2014), 123 (6), 905-913CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)Upregulation of Pim kinases is obsd. in several types of leukemias and lymphomas. Pim-1, -2, and -3 promote cell proliferation and survival downstream of cytokine and growth factor signaling pathways. AZD1208 is a potent, highly selective, and orally available Pim kinase inhibitor that effectively inhibits all three isoforms at <5 nM or <150 nM in enzyme and cell assays, resp. AZD1208 inhibited the growth of 5 of 14 acute myeloid leukemia (AML) cell lines tested, and sensitivity correlates with Pim-1 expression and STAT5 activation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells, accompanied by a dose-dependent redn. in phosphorylation of Bcl-2 antagonist of cell death, 4EBP1, p70S6K, and S6, as well as increases in cleaved caspase 3 and p27. Inhibition of p4EBP1 and p-p70S6K and suppression of translation are the most representative effects of Pim inhibition in sensitive AML cell lines. AZD1208 inhibits the growth of MOLM-16 and KG-1a xenograft tumors in vivo with a clear pharmacodynamic-pharmacokinetic relationship. AZD1208 also potently inhibits colony growth and Pim signaling substrates in primary AML cells from bone marrow that are Flt3 wild-type or Flt3 internal tandem duplication mutant. These results underscore the therapeutic potential of Pim kinase inhibition for the treatment of AML.
- 302Pan, Z.; Scheerens, H.; Li, S. J.; Schultz, B. E.; Sprengeler, P. A.; Burrill, L. C.; Mendonca, R. V.; Sweeney, M. D.; Scott, K. C. K.; Grothaus, P. G.; Jeffery, D. A.; Spoerke, J. M.; Honigberg, L. A.; Young, P. R.; Dalrymple, S. A.; Palmer, J. T. Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase ChemMedChem 2007, 2, 58– 61 DOI: 10.1002/cmdc.200600221[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsVWjsbg%253D&md5=023ba8bca9942ad0127d7cf32293e9d2Discovery of selective irreversible inhibitors for bruton's tyrosine kinasePan, Zhengying; Scheerens, Heleen; Li, Shyr-Jiann; Schultz, Brian E.; Sprengeler, Paul A.; Burrill, L. Chuck; Mendonca, Rohan V.; Sweeney, Michael D.; Scott, Keana C. K.; Grothaus, Paul G.; Jeffery, Douglas A.; Spoerke, Jill M.; Honigberg, Lee A.; Young, Peter R.; Dalrymple, Stacie A.; Palmer, James T.ChemMedChem (2007), 2 (1), 58-61CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Synthesis and pharmacol. evaluation of a series of peptidomimetic quinoline derivs. was undertaken to evaluate their efficacy in acting as selective irreversible inhibitors of Bruton's tyrosine kinase (Btk). With the relative scarcity of knowledge on the inhibition of Btk it is crucial to discover a potent and selective tool compd. for this kinase. Herein is described the discovery of selective irreversible Btk inhibitors and their efficacy in a mouse RA model.
- 303Bernard, S.; Goldwirt, L.; Amorim, S.; Brice, P.; Bnere, J.; de Kerviller, E.; Mourah, S.; Sauvageon, H.; Thieblemont, C. Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse Blood 2015, 126, 1695– 1698 DOI: 10.1182/blood-2015-05-647834
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- 305(a) Biddlestone-Thorpe, L.; Sajjad, M.; Rosenberg, E.; Beckta, J. M.; Valerie, N. C. K.; Tokarz, M.; Adams, B. R.; Wagner, A. F.; Khalil, A.; Gilfor, D.; Golding, S. E.; Deb, S.; Temesi, D. G.; Lau, A.; O’Connor, M. J.; Choe, K. S.; Parada, L. F.; Lim, S. K.; Mukhopadhyay, N. D.; Valerie, K. ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation Clin. Cancer Res. 2013, 19, 3189– 3200 DOI: 10.1158/1078-0432.CCR-12-3408[Crossref], [PubMed], [CAS], Google Scholar305ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpsVynsL4%253D&md5=b77a60ce3d07e969f3cacb897676e6f8ATM Kinase Inhibition Preferentially Sensitizes p53-Mutant Glioma to Ionizing RadiationBiddlestone-Thorpe, Laura; Sajjad, Muhammad; Rosenberg, Elizabeth; Beckta, Jason M.; Valerie, Nicholas C. K.; Tokarz, Mary; Adams, Bret R.; Wagner, Alison F.; Khalil, Ashraf; Gilfor, Donna; Golding, Sarah E.; Deb, Sumitra; Temesi, David G.; Lau, Alan; O'Connor, Mark J.; Choe, Kevin S.; Parada, Luis F.; Lim, Sang Kyun; Mukhopadhyay, Nitai D.; Valerie, KristofferClinical Cancer Research (2013), 19 (12), 3189-3200CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival of only 12 to 15 mo. Current std. treatment consists of surgery followed by chemoradiation. The poor survival of patients with GBM is due to aggressive tumor invasiveness, an inability to remove all tumor tissue, and an innate tumor chemo- and radioresistance. Ataxia-telangiectasia mutated (ATM) is an excellent target for radiosensitizing GBM because of its crit. role in regulating the DNA damage response and p53, among other cellular processes. As a first step toward this goal, we recently showed that the novel ATM kinase inhibitor KU-60019 reduced migration, invasion, and growth, and potently radiosensitized human glioma cells in vitro. Exptl. Design: Using orthotopic xenograft models of GBM, we now show that KU-60019 is also an effective radiosensitizer in vivo. Human glioma cells expressing reporter genes for monitoring tumor growth and dispersal were grown intracranially, and KU-60019 was administered intratumorally by convection-enhanced delivery or osmotic pump. Results: Our results show that the combined effect of KU-60019 and radiation significantly increased survival of mice 2- to 3-fold over controls. Importantly, we show that glioma with mutant p53 is much more sensitive to KU-60019 radiosensitization than genetically matched wild-type glioma. Conclusions: Taken together, our results suggest that an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers. Clin Cancer Res; 19(12); 3189-200. ©2013 AACR.(b) Nadkarni, A.; Shrivastav, M.; Mladek, A. C.; Schwingler, P. M.; Grogan, P. T.; Chen, J.; Sarkaria, J. N. ATM inhibitor Ku-55993 increases the TMZ responsiveness of only inherently TMZ sensitive GBM cells J. Neuro-Oncol. 2012, 110, 349– 357 DOI: 10.1007/s11060-012-0979-0[Crossref], [PubMed], [CAS], Google Scholar305bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs12rs7bI&md5=be2aa0965dab757cd6d61cb83143c905ATM inhibitor KU-55933 increases the TMZ responsiveness of only inherently TMZ sensitive GBM cellsNadkarni, Aditi; Shrivastav, Meena; Mladek, Ann C.; Schwingler, Paul M.; Grogan, Patrick T.; Chen, Junjie; Sarkaria, Jann N.Journal of Neuro-Oncology (2012), 110 (3), 349-357CODEN: JNODD2; ISSN:0167-594X. (Springer)Ataxia telangiectasia mutated (ATM) kinase is crit. in sensing and repairing DNA double-stranded breaks (DSBs) such as those induced by temozolomide (TMZ). ATM deficiency increases TMZ sensitivity, which suggests that ATM inhibitors may be effective TMZ sensitizing agents. In this study, the TMZ sensitizing effects of 2 ATM specific inhibitors were studied in established and xenograft-derived glioblastoma (GBM) lines that are inherently sensitive to TMZ and deriv. TMZ-resistant lines. In parental U251 and U87 glioma lines, the addn. of KU-55933 to TMZ significantly increased cell killing compared to TMZ alone [U251 survival: 0.004 ± 0.0015 vs. 0.08 ± 0.01 (p < 0.001), resp., and U87 survival: 0.02 ± 0.005 vs. 0.04 ± 0.002 (p < 0.001), resp.] and also elevated the fraction of cells arrested in G2/M [U251 G2/M fraction: 61.8 ± 1.1 % vs. 35 ± 0.8 % (p < 0.001), resp., and U87 G2/M fraction 25 ± 0.2 % vs.18.6 ± 0.4 % (p < 0.001), resp.]. In contrast, KU-55933 did not sensitize the resistant lines to TMZ, and neither TMZ alone or combined with KU-55933 induced a G2/M arrest. While KU-55933 did not enhance TMZ induced Chk1/Chk2 activation, it increased TMZ-induced residual γ-H2AX foci in the parental cells but not in the TMZ resistant cells. Similar sensitization was obsd. with either KU-55933 or CP-466722 combined with TMZ in GBM12 xenograft line but not in GBM12TMZ, which is resistant to TMZ due to MGMT overexpression. These findings are consistent with a model where ATM inhibition suppresses the repair of TMZ-induced DSBs in inherently TMZ-sensitive tumor lines, which suggests an ATM inhibitor potentially could be deployed with an improvement in the therapeutic window when combined with TMZ.
- 306Linger, R. M. A.; Keating, A. K.; Earp, H. Sh.; Graham, D. K. Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors Expert Opin. Ther. Targets 2010, 14, 1073– 1090 DOI: 10.1517/14728222.2010.515980[Crossref], [PubMed], [CAS], Google Scholar306https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFOktL3I&md5=078559de448e07d9360eaff2b167ddefTaking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumorsLinger, Rachel M. A.; Keating, Amy K.; Earp, H. Shelton; Graham, Douglas K.Expert Opinion on Therapeutic Targets (2010), 14 (10), 1073-1090CODEN: EOTTAO; ISSN:1472-8222. (Informa Healthcare)A review. Importance of the field: Axl and/or Mer expression correlates with poor prognosis in several cancers. Until recently, the role of these receptor tyrosine kinases (RTKs) in development and progression of cancer remained unexplained. Studies demonstrating that Axl and Mer contribute to cell survival, migration, invasion, metastasis and chemosensitivity justify further investigation of Axl and Mer as novel therapeutic targets in cancer. Areas covered in this review: Axl and Mer signaling pathways in cancer cells are summarized and evidence validating these RTKs as therapeutic targets in glioblastoma multiforme, NSCLC, and breast cancer is examd. A discussion of Axl and/or Mer inhibitors in development is provided.What the reader will gain: Potential toxicities assocd. with Axl or Mer inhibition are addressed. We propose that the probable action of Mer and Axl inhibitors on cells within the tumor microenvironment will provide a therapeutic opportunity to target both tumor cells and the stromal components that facilitate disease progression. Take home message: Axl and Mer mediate multiple oncogenic phenotypes and activation of these RTKs constitutes a mechanism of chemoresistance in a variety of solid tumors. Targeted inhibition of these RTKs may be effective as anti-tumor and/or anti-metastatic therapy, particularly if combined with std. cytotoxic therapies.
- 307Joshi, A. D.; Loilome, W.; Siu, I.-M.; Tyler, B.; Gallia, G. L.; Riggins, G. J. Evaluation of tyrosine kinase inhibitor combinations for glioblastoma therapy PLoS One 2012, 7, e44372 DOI: 10.1371/journal.pone.0044372
As an example of the potential importance of inhibiting multiple kinases:
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See Supporting Information for details of individual inhibitors.
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Abstract
Figure 1
Figure 1. Structural modifications upon gefitinib (17), focused on reducing rotatable bonds and effective hydrogen bond donors, led to the freely BBB penetrating inhibitor of EGFR, 22.
Figure 2
Figure 2. Modifications of PI3K/mTOR inhibitors that resulted in the discovery of 25, a brain penetrating inhibitor with desirable metabolic stability.
Figure 3
Figure 3. Macrocyclization led to improved metabolic stability, potency, and reduced P-gp mediated efflux in this series of ALK inhibitors.
Figure 4
Figure 4. Reducing effective HBD count by intramolecular hydrogen bonding reduced P-gp efflux among a set of PLK1 inhibitors.
References
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- 3Patchell, R. A. The management of brain metastases Cancer Treat. Rev. 2003, 29, 533– 540 DOI: 10.1016/S0305-7372(03)00105-1[Crossref], [PubMed], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3srgvV2lsA%253D%253D&md5=1ff0aef5208905634eddf4268bf70dbbThe management of brain metastasesPatchell Roy ACancer treatment reviews (2003), 29 (6), 533-40 ISSN:0305-7372.Brain metastases are neoplasms that originate in tissues outside the brain and then spread secondarily to the brain. Metastases to the brain are the most common intracranial tumours in adults. Substantial progress has been made in the treatment of these tumours, and radiotherapy, surgery, and stereotactic radiosurgery are now established treatments. With aggressive treatment, most patients experience meaningful symptom reduction and extension of life.
- 4Swain, S. M.; Baselga, J.; Miles, D.; Im, Y.-H.; Quah, C.; Lee, L. F.; Cortes, J. Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA Ann. Oncol. 2014, 25, 1116– 1121 DOI: 10.1093/annonc/mdu133[Crossref], [PubMed], [CAS], Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crovF2kug%253D%253D&md5=3977a226c42d9331d0d37e546f832224Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRASwain S M; Baselga J; Miles D; Im Y-H; Quah C; Lee L F; Cortes JAnnals of oncology : official journal of the European Society for Medical Oncology / ESMO (2014), 25 (6), 1116-21 ISSN:.BACKGROUND: Results from the phase III trial CLEOPATRA in human epidermal growth factor receptor 2-positive first-line metastatic breast cancer demonstrated significant improvements in progression-free and overall survival with pertuzumab, trastuzumab, and docetaxel over placebo, trastuzumab, and docetaxel. We carried out exploratory analyses of the incidence and time to development of central nervous system (CNS) metastases in patients from CLEOPATRA. PATIENTS AND METHODS: Patients received pertuzumab/placebo: 840 mg in cycle 1, then 420 mg; trastuzumab: 8 mg/kg in cycle 1, then 6 mg/kg; docetaxel: initiated at 75 mg/m(2). Study drugs were administered i.v. every 3 weeks. The log-rank test was used for between-arm comparisons of time to CNS metastases as first site of disease progression and overall survival in patients with CNS metastases as first site of disease progression. The Kaplan-Meier approach was used to estimate median time to CNS metastases as first site of disease progression and median overall survival. RESULTS: The incidence of CNS metastases as first site of disease progression was similar between arms; placebo arm: 51 of 406 (12.6%), pertuzumab arm: 55 of 402 (13.7%). Median time to development of CNS metastases as first site of disease progression was 11.9 months in the placebo arm and 15.0 months in the pertuzumab arm; hazard ratio (HR) = 0.58, 95% confidence interval (CI) 0.39-0.85, P = 0.0049. Overall survival in patients who developed CNS metastases as first site of disease progression showed a trend in favor of pertuzumab, trastuzumab, and docetaxel; HR = 0.66, 95% CI 0.39-1.11. Median overall survival was 26.3 versus 34.4 months in the placebo and pertuzumab arms, respectively. Treatment comparison of the survival curves was not statistically significant for the log-rank test (P = 0.1139), but significant for the Wilcoxon test (P = 0.0449). CONCLUSIONS: While the incidence of CNS metastases was similar between arms, our results suggest that pertuzumab, trastuzumab, and docetaxel delays the onset of CNS disease compared with placebo, trastuzumab, and docetaxel. CLINICALTRIALSGOV: NCT00567190.
- 5(a) Mehta, M. P.; Paleologos, N. A.; Mikkelsen, T.; Robinson, P. D.; Ammirati, M.; Andrews, D. W.; Asher, A. L.; Burri, S. H.; Cobbs, C. S.; Gaspar, L. E.; Kondziolka, D.; Linskey, M. E.; Loeffler, J. S.; McDermott, M.; Olson, J. J.; Patchell, R. A.; Ryken, T. C.; Kalkanis, S. N. The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline J. Neuro-Oncol. 2010, 96, 71– 83 DOI: 10.1007/s11060-009-0062-7[Crossref], [PubMed], [CAS], Google Scholar5ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c%252FktFSisQ%253D%253D&md5=c39c3c487f2ed14d1e1d2f844fee0da3The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guidelineMehta Minesh P; Paleologos Nina A; Mikkelsen Tom; Robinson Paula D; Ammirati Mario; Andrews David W; Asher Anthony L; Burri Stuart H; Cobbs Charles S; Gaspar Laurie E; Kondziolka Douglas; Linskey Mark E; Loeffler Jay S; McDermott Michael; Olson Jeffrey J; Patchell Roy A; Ryken Timothy C; Kalkanis Steven NJournal of neuro-oncology (2010), 96 (1), 71-83 ISSN:.TARGET POPULATION: This recommendation applies to adults with newly diagnosed brain metastases; however, the recommendation below does not apply to the exquisitely chemosensitive tumors, such as germinomas metastatic to the brain. RECOMMENDATION: Should patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT)? Level 1 Routine use of chemotherapy following WBRT for brain metastases has not been shown to increase survival and is not recommended. Four class I studies examined the role of carboplatin, chloroethylnitrosoureas, tegafur and temozolomide, and all resulted in no survival benefit. Two caveats are provided in order to allow the treating physician to individualize decision-making: First, the majority of the data are limited to non small cell lung (NSCLC) and breast cancer; therefore, in other tumor histologies, the possibility of clinical benefit cannot be absolutely ruled out. Second, the addition of chemotherapy to WBRT improved response rates in some, but not all trials; response rate was not the primary endpoint in most of these trials and end-point assessment was non-centralized, non-blinded, and post-hoc. Enrollment in chemotherapy-related clinical trials is encouraged.(b) Owonikoko, T. K.; Arbiser, J.; Zelnak, A.; Shu, H.-K. G.; Shim, H.; Robin, A. M.; Kalkanis, S. N.; Whitsett, T. G.; Salhia, B.; Tran, N. L.; Ryken, T.; Moore, M. K.; Egan, K.; Olson, J. J. Current approaches to the treatment of metastatic brain tumors Nat. Rev. Clin. Oncol. 2014, 11, 203– 222 DOI: 10.1038/nrclinonc.2014.25[Crossref], [PubMed], [CAS], Google Scholar5bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjsVChsrY%253D&md5=499d772b17c0f7a323ddbdb7cfd88341Current approaches to the treatment of metastatic brain tumoursOwonikoko, Taofeek K.; Arbiser, Jack; Zelnak, Amelia; Shu, Hui-Kuo G.; Shim, Hyunsuk; Robin, Adam M.; Kalkanis, Steven N.; Whitsett, Timothy G.; Salhia, Bodour; Tran, Nhan L.; Ryken, Timothy; Moore, Michael K.; Egan, Kathleen M.; Olson, Jeffrey J.Nature Reviews Clinical Oncology (2014), 11 (4), 203-222CODEN: NRCOAA; ISSN:1759-4774. (Nature Publishing Group)A review. Metastatic tumors involving the brain overshadow primary brain neoplasms in frequency and are an important complication in the overall management of many cancers. Importantly, advances are being made in understanding the mol. biol. underlying the initial development and eventual proliferation of brain metastases. Surgery and radiation remain the cornerstones of the therapy for symptomatic lesions; however, image-based guidance is improving surgical technique to maximize the preservation of normal tissue, while more sophisticated approaches to radiation therapy are being used to minimize the long-standing concerns over the toxicity of whole-brain radiation protocols used in the past. Furthermore, the burgeoning knowledge of tumor biol. has facilitated the entry of systemically administered therapies into the clinic. Responses to these targeted interventions have ranged from substantial toxicity with no control of disease to periods of useful tumor control with no decrement in performance status of the treated individual. This experience enables recognition of the limits of targeted therapy, but has also informed methods to optimize this approach. This Review focuses on the clin. relevant mol. biol. of brain metastases, and summarizes the current applications of these data to imaging, surgery, radiation therapy, cytotoxic chemotherapy and targeted therapy.
- 6(a) Steeg, P. S.; Camphausen, K. A.; Smith, Q. R. Brain metastases as preventive and therapeutic targets Nat. Rev. Cancer 2011, 11, 352– 363 DOI: 10.1038/nrc3053[Crossref], [PubMed], [CAS], Google Scholar6ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXksVCrtro%253D&md5=b45316ddf5f3ce9a04076157365831b7Brain metastases as preventive and therapeutic targetsSteeg, Patricia S.; Camphausen, Kevin A.; Smith, Quentin R.Nature Reviews Cancer (2011), 11 (5), 352-363CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. The brain is considered a 'sanctuary site' as the blood-tumor barrier limits the ability of drugs to enter and kill tumor cells. Translational research examg. metastasis to the brain needs to be multi-disciplinary, marrying advanced chem., blood-brain barrier pharmacokinetics, neurocognitive testing and radiation biol. with metastasis biol., to develop and implement new clin. trial designs. Advances in the chemoprevention of brain metastases, the validation of tumor radiation sensitizers and the amelioration of cognitive deficits caused by whole-brain radiation therapy are discussed.(b) Sledge, G. W. Heading in a new direction: drug permeability in breast cancer brain metastasis Clin. Cancer Res. 2010, 16, 5605– 5607 DOI: 10.1158/1078-0432.CCR-10-2502[Crossref], [PubMed], [CAS], Google Scholar6bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M%252Fitl2lsQ%253D%253D&md5=c4bc748744757ff9720aeabdbff16e60Heading in a new direction: drug permeability in breast cancer brain metastasisSledge George W JrClinical cancer research : an official journal of the American Association for Cancer Research (2010), 16 (23), 5605-7 ISSN:1078-0432.Systemic therapies for breast cancer brain metastasis are largely unsuccessful. Mouse models of brain metastasis show significant heterogeneity in uptake of paclitaxel and doxorubicin, with average levels more than those seen in normal brain tissue, but significantly less than in metastases to other organs.(c) Lockman, P. R.; Mittapalli, R. K.; Taskar, K. S.; Rudraraju, V.; Gril, B.; Bohn, K. A.; Adkins, C. E.; Roberts, A.; Thorsheim, H. R.; Gaasch, J. A.; Huang, S.; Palmien, D.; Steeg, P. S.; Smith, Q. R. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer Clin. Cancer Res. 2010, 16, 5664– 5678 DOI: 10.1158/1078-0432.CCR-10-1564[Crossref], [PubMed], [CAS], Google Scholar6chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFamtL3F&md5=f14491d5c3f4a345b4114c348632916cHeterogeneous Blood-Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast CancerLockman, Paul R.; Mittapalli, Rajendar K.; Taskar, Kunal S.; Rudraraju, Vinay; Gril, Brunilde; Bohn, Kaci A.; Adkins, Chris E.; Roberts, Amanda; Thorsheim, Helen R.; Gaasch, Julie A.; Huang, Suyun; Palmieri, Diane; Steeg, Patricia S.; Smith, Quentin R.Clinical Cancer Research (2010), 16 (23), 5664-5678CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)PURPOSE: Brain metastases of breast cancer appear to be increasing in incidence, confer significant morbidity, and threaten to compromise gains made in systemic chemotherapy. The blood-tumor barrier (BTB) is compromised in many brain metastases; however, the extent to which this influences chemotherapeutic delivery and efficacy is unknown. Herein, we answer this question by measuring BTB passive integrity, chemotherapeutic drug uptake, and anticancer efficacy in vivo in two breast cancer models that metastasize preferentially to brain. Exptl. Design:Exptl. brain metastasis drug uptake and BTB permeability were simultaneously measured using novel fluorescent and phosphorescent imaging techniques in immune-compromised mice. Drug-induced apoptosis and vascular characteristics were assessed using immunofluorescent microscopy. RESULTS: Anal. of over 2,000 brain metastases from two models (human 231-BR-Her2 and murine 4T1-BR5) showed partial BTB permeability compromise in greater than 89% of lesions, varying in magnitude within and between metastases. Brain metastasis uptake of 14C-paclitaxel and 14C-doxorubicin was generally greater than normal brain but less than 15% of that of other tissues or peripheral metastases, and only reached cytotoxic concns. in a small subset (∼10%) of the most permeable metastases. Neither drug significantly decreased the exptl. brain metastatic ability of 231-BR-Her2 tumor cells. BTB permeability was assocd. with vascular remodeling and correlated with overexpression of the pericyte protein desmin. CONCLUSIONS: This work shows that the BTB remains a significant impediment to std. chemotherapeutic delivery and efficacy in exptl. brain metastases of breast cancer. New brain permeable drugs will be needed. Evidence is presented for vascular remodeling in BTB permeability alterations. Clin Cancer Res; 16(23); 5664-78.(d) Henson, J. W.; Cordon-Cardo, C.; Posner, J. B. P-glycoprotein expression in brain tumors J. Neuro-Oncol. 1992, 14, 37– 43 DOI: 10.1007/BF00170943[Crossref], [PubMed], [CAS], Google Scholar6dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3s7gvVSguw%253D%253D&md5=be90a5093bf829cba5e21c4a5a5eb321P-glycoprotein expression in brain tumorsHenson J W; Cordon-Cardo C; Posner J BJournal of neuro-oncology (1992), 14 (1), 37-43 ISSN:0167-594X.Overexpression of P-glycoprotein (P-gp) in cancer cells can result in resistance to several chemotherapy agents (multidrug resistance) including doxorubicin and vincristine. The drugs to which resistance develops also penetrate the blood brain barrier poorly. P-gp expression in brain capillary endothelial cells suggests that P-gp may restrict drug entry into brain tumors and thus be another mechanism of drug resistance. To seek evidence for either of these roles in the drug resistance of brain tumors, we examined the location of expression of P-gp in 49 brain tumors, using an anti-P-gp mouse monoclonal antibody and immunohistochemistry. P-gp expression was observed in tumor cells of two glioblastomas and a meningeal sarcoma but not in low-grade primary or metastatic tumors. In low-grade primary tumors, P-gp was present in all vascular endothelial cells. In the vascular endothelial cells of anaplastic primary brain tumors and brain metastases, P-gp expression was heterogeneous or absent. These findings are consistent with a role for P-gp in the resistance of some brain tumors to chemotherapy agents.(e) Demeule, M.; Shedid, D.; Beaulieu, E.; Del Maestro, R. F.; Moghrabi, A.; Ghosn, P. B.; Moumdijian, R.; Berthelet, F.; Beliveau, R. Expression of multidrug-resistance P-glycoprotein (MDR1) in human brain tumors Int. J. Cancer 2001, 93, 62– 66 DOI: 10.1002/ijc.1306[Crossref], [PubMed], [CAS], Google Scholar6ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXksFanur0%253D&md5=de070fb54c77cf4a556f8c581e27295dExpression of multidrug-resistance P-glycoprotein (MDR1) in human brain tumorsDemeule, Michel; Shedid, Daniel; Beaulieu, Edith; Del Maestro, Rolando F.; Moghrabi, Albert; Ghosn, Pierre B.; Moumdjian, Robert; Berthelet, France; Beliveau, RichardInternational Journal of Cancer (2001), 93 (1), 62-66CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)Multidrug resistance (MDR) is assocd. with the expression of P-glycoprotein (P-gp), an ATP-dependent transporter which expels anti-cancer drugs from cells. In the present study, MDR1 P-gp was immunodetected by Western blot anal. in 60 human brain tumors, including meningiomas, schwannomas, low-grade gliomas (astrocytomas, pilocytic astrocytomas) and high-grade gliomas (anaplastic astrocytomas, glioblastomas and anaplastic oligodendrogliomas). Most samples from primary tumors expressed P-gp at the same levels as normal brain tissue except for schwannomas, in which levels were reduced by 65%, and meningiomas, in which levels were more than 10-fold higher in 7 of 10 samples. P-gp levels were 70% and 95% lower in brain metastases from melanomas and lung adenocarcinomas, resp., than in normal brain tissue. These results indicate that the majority of primary brain tumors express MDR1 P-gp and that its high expression levels in meningiomas may be a marker for this type of brain tumor.
- 7(a) Claes, A.; Idema, A. J.; Wesseling, P. Diffuse glioma growth: a guerrila war Acta Neuropathol. 2007, 114, 443– 448 DOI: 10.1007/s00401-007-0293-7[Crossref], [PubMed], [CAS], Google Scholar7ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2srovFamuw%253D%253D&md5=41a660215dccbe502b7fabf5b04867baDiffuse glioma growth: a guerilla warClaes An; Idema Albert J; Wesseling PieterActa neuropathologica (2007), 114 (5), 443-58 ISSN:0001-6322.In contrast to almost all other brain tumors, diffuse gliomas infiltrate extensively in the neuropil. This growth pattern is a major factor in therapeutic failure. Diffuse infiltrative glioma cells show some similarities with guerilla warriors. Histopathologically, the tumor cells tend to invade individually or in small groups in between the dense network of neuronal and glial cell processes. Meanwhile, in large areas of diffuse gliomas the tumor cells abuse pre-existent "supply lines" for oxygen and nutrients rather than constructing their own. Radiological visualization of the invasive front of diffuse gliomas is difficult. Although the knowledge about migration of (tumor)cells is rapidly increasing, the exact molecular mechanisms underlying infiltration of glioma cells in the neuropil have not yet been elucidated. As the efficacy of conventional methods to fight diffuse infiltrative glioma cells is limited, a more targeted ("search & destroy") tactic may be needed for these tumors. Hopefully, the study of original human glioma tissue and of genotypically and phenotypically relevant glioma models will soon provide information about the Achilles heel of diffuse infiltrative glioma cells that can be used for more effective therapeutic strategies.(b) Agarwal, S.; Sane, R.; Oberoi, R.; Ohlfest, J. R.; Elmquist, W. F. Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain Expert Rev. Mol. Med. 2011, 13, e17 DOI: 10.1017/S1462399411001888[Crossref], [PubMed], [CAS], Google Scholar7bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXms1OksLw%253D&md5=64ddd4cf91c94640ec2d1e548924383cDelivery of molecularly targeted therapy to malignant glioma, a disease of the whole brainAgarwal, Sagar; Sane, Ramola; Oberoi, Rajneet; Ohlfest, John R.; Elmquist, William F.Expert Reviews in Molecular Medicine (2011), 13 (), e17/1-e17/17CODEN: ERMMFS; ISSN:1462-3994. (Cambridge University Press)A review. Glioblastoma multiforme, because of its invasive nature, can be considered a disease of the entire brain. Despite recent advances in surgery, radiotherapy and chemotherapy, current treatment regimens have only a marginal impact on patient survival. A crucial challenge is to deliver drugs effectively to invasive glioma cells residing in a sanctuary within the central nervous system. The blood-brain barrier (BBB) restricts the delivery of many small and large mols. into the brain. Drug delivery to the brain is further restricted by active efflux transporters present at the BBB. Current clin. assessment of drug delivery and hence efficacy is based on the measured drug levels in the bulk tumor mass that is usually removed by surgery. Mounting evidence suggests that the inevitable relapse and lethality of glioblastoma multiforme is due to a failure to effectively treat invasive glioma cells. These invasive cells hide in areas of the brain that are shielded by an intact BBB, where they continue to grow and give rise to the recurrent tumor. Effective delivery of chemotherapeutics to the invasive glioma cells is therefore crit., and long-term efficacy will depend on the ability of a molecularly targeted agent to penetrate an intact and functional BBB throughout the entire brain. This review highlights the various aspects of the BBB, and also the brain-tumor-cell barrier (a barrier due to expression of efflux transporters in tumor cells), that together can significantly influence drug response. It then discusses the challenge of glioma as a disease of the whole brain, which lends emphasis to the need to deliver drugs effectively across the BBB to reach both the central tumor and the invasive glioma cells.(c) Kuratsu, J.; Itoyama, Y.; Uemura, S.; Ushio, Y. Regrowth patterns of glioma—cases of glioma regrew away from the original tumor Gan No Rinsho 1989, 35, 1255– 1260[PubMed], [CAS], Google Scholar7chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3c%252FktFemsw%253D%253D&md5=079ef2db2deab51b57f353b53d2db65aRegrowth patterns of glioma--cases of glioma regrew away from the original tumorKuratsu J; Itoyama Y; Uemura S; Ushio YGan no rinsho. Japan journal of cancer clinics (1989), 35 (11), 1255-60 ISSN:0021-4949.There have been conflicting opinions regarding the correct volume to be used in radiotherapy fields for malignant glioma. Whereas many clinicians recommend limited fields designed to cover the tumor volume with a margin according to the facts about 90% of recurrent malignant glioma regrew within 2 cm of the original tumor and regrowth away from the original tumor was seen in about 5%. Two cases of malignant glioma regrew away for the original tumor and one case of malignant glioma regrew into the resected site were presented. And the biological characteristics of glioma cells concerning with the invasiveness were discussed.(d) Silbergeld, D. L.; Chicoine, M. R. Isolation and characterization of human malignant glioma cells from histologically normal brain J. Neurosurg. 1997, 86, 525– 531 DOI: 10.3171/jns.1997.86.3.0525[Crossref], [PubMed], [CAS], Google Scholar7dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s7pvVamtQ%253D%253D&md5=922c50772af913db88f8112415eabd16Isolation and characterization of human malignant glioma cells from histologically normal brainSilbergeld D L; Chicoine M RJournal of neurosurgery (1997), 86 (3), 525-31 ISSN:0022-3085.Brain invasion prevents complete surgical extirpation of malignant gliomas; however, invasive cells from distant, histologically normal brain previously have not been isolated, cultured, and characterized. To evaluate invasive human malignant glioma cells, the authors established cultures from gross tumor and histologically normal brain. Three men and one woman, with a mean age of 67 years, underwent two frontal and two temporal lobectomies for tumors, which yielded specimens of both gross tumor and histologically normal brain. Each specimen was acquired a minimum of 4 cm from the gross tumor. The specimens were split: a portion was sent for neuropathological evaluation (three glioblastomas multiforme and one oligodendroglioma) and a portion was used to establish cell lines. Morphologically, the specimens of gross tumor and histologically normal brain were identical in three of the four cell culture pairs. Histochemical staining characteristics were consistent both within each pair and when compared with the specimens sent for neuropathological evaluation. Cultures demonstrated anchorage-independent growth in soft agarose and neoplastic karyotypes. Growth rates in culture were greater for histologically normal brain than for gross tumor in three of the four culture pairs. Although the observed increases in growth rates of histologically normal brain cultures do not correlate with in vivo behavior, these findings corroborate the previously reported stem cell potential of invasive glioma cells. Using the radial dish assay, no significant differences in motility between cultures of gross tumor and histologically normal brain were found. In summary, tumor cells were cultured from histologically normal brain acquired from a distance greater than 4 cm from the gross tumor, indicating the relative insensitivity of standard histopathological identification of invasive glioma cells (and hence the inadequacy of frozen-section evaluation of resection margins). Cell lines derived from gross tumor and histologically normal brain were usually histologically identical and demonstrated equivalent motility, but had different growth rates.(e) Lucio-Eterovic, A. K.; Piao, Y.; de Groot, J. F. Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy Clin. Cancer Res. 2009, 15, 4589– 4599 DOI: 10.1158/1078-0432.CCR-09-0575[Crossref], [PubMed], [CAS], Google Scholar7ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosV2lt7Y%253D&md5=804ce893168284aa1a95abac77e8b92cMediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapyLucio-Eterovic, Agda K.; Piao, Yuji; de Groot, John F.Clinical Cancer Research (2009), 15 (14), 4589-4599CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)PURPOSE: Vascular endothelial growth factor (VEGF) has been identified as a crit. regulator of angiogenesis. Currently, several different strategies are being used to target the VEGF-VEGF receptor signal transduction pathway in glioblastoma. Although anti-VEGF therapy seems be effective in normalizing abnormal tumor vasculature, leading to an enhanced response to radiation and chemotherapy, tumors eventually become resistant to the therapy and adopt a highly infiltrative and invasive phenotype. Exptl. Design: In the present study, we evaluated the effects of anti-VEGF therapy (bevacizumab) on glioblastoma invasion both in vitro and in vivo and evaluated the angiogenesis- and invasion-related mediators of developed resistance to this therapy. RESULTS: We found that glioblastoma tumors escaped from antiangiogenic treatment by (a) reactivating angiogenesis through up-regulation of other proangiogenic factors and (b) invading normal brain areas, which was seen in assocn. with up-regulation of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-12; secreted protein, acidic, cysteine-rich; and tissue inhibitor of metalloproteinase 1. In addn. to the paracrine effects of VEGF on endothelial cells, autocrine VEGF signaling seemed to regulate glioblastoma invasion because anti-VEGF therapy increased tumor invasiveness in vitro. CONCLUSIONS: Collectively, these findings reinforce the importance of VEGF in regulating tumor invasion and identify potential mediators of resistance to targeted VEGF therapy. These results will be important for developing novel combination therapies to overcome this resistance phenotype.
- 8Rankovic, Z. CNS Drug Design: Balancing physicochemical properties for optimal brain exposure J. Med. Chem. 2015, 58, 2584– 2608 DOI: 10.1021/jm501535r[ACS Full Text], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVyhsrrP&md5=f01e3f2dc4e2eff7b0618124277a5cf8CNS Drug Design: Balancing Physicochemical Properties for Optimal Brain ExposureRankovic, ZoranJournal of Medicinal Chemistry (2015), 58 (6), 2584-2608CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing mols. that can overcome this protection system and achieve optimal concn. at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochem. properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most crit. physicochem. and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chem. strategies toward mols. with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided.
- 9Levin, V. A.; Tonge, P. T.; Gallo, J. M.; Birtwistle, M. R.; Dar, A. C.; Iavarone, A.; Paddison, P. J.; Heffron, T. P.; Elmquist, W. F.; Lachowicz, J. E.; Johnson, T. W.; White, F. M.; Sul, J.; Smith, Q. R.; Shen, W.; Sarkaria, J. N.; Samala, R.; Wen, P. Y.; Berry, D. A.; Petter, R. C. CNS anticancer drug discovery and development conference white paper Neuro-Oncology 2015, 17, vi1– vi26 DOI: 10.1093/neuonc/nov169
- 10(a) Sun, H.; Dai, H.; Shaik, N.; Elmquist, W. F. Drug efflux transporters in the CNS Adv. Drug Delivery Rev. 2003, 55, 83– 105 DOI: 10.1016/S0169-409X(02)00172-2(b) He, H.; Lyons, K. A.; Shen, X.; Yao, Z.; Bleasby, K.; Chan, G.; Hafey, M.; Li, X.; Xu, S.; Salituro, G. M.; Cohen, L. H.; Tang, W. Utility of unbound plasma drug levels and P-glycoprotein transport data in prediction of central nervous system exposure Xenobiotica 2009, 39, 687– 693 DOI: 10.1080/00498250903015402[Crossref], [PubMed], [CAS], Google Scholar10bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXps12gtbs%253D&md5=f9b7ad759a8ced86e9b8b90c445217f3Utility of unbound plasma drug levels and P-glycoprotein transport data in prediction of central nervous system exposureHe, H.; Lyons, K. A.; Shen, X.; Yao, Z.; Bleasby, K.; Chan, G.; Hafey, M.; Li, X.; Xu, S.; Salituro, G. M.; Cohen, L. H.; Tang, W.Xenobiotica (2009), 39 (9), 687-693CODEN: XENOBH; ISSN:0049-8254. (Informa Healthcare)Drug concns. in cerebrospinal fluid were assumed to be a natural surrogate for total drug exposures in the central nervous system. The present communication reports a data set from a study of 30 compds. in mice. An attempt was made to correlate cerebrospinal fluid and unbound plasma drug concns. via incorporation of in vitro P-glycoprotein (Pgp)-mediated transport data. Pgp-deficient (Pgp -/-) and wild-type mice were dosed with compds. of interest by oral gavage (orally) at 5 mg kg-1. Plasma and cerebrospinal fluid samples were collected at 1h post-dosing, and analyzed by liq. chromatog.-tandem mass spectrometry (LC-MS/MS) for drug concns. Mouse and human Pgp-mediated transport were evaluated in vitro by a bi-directional (B to A and A to B) transport assay using LLC-PK1 cells expressing mouse (mdr1a) and human (MDR1) forms of Pgp, resp. Compds. with B to A/A to B transport ratios <2 were defined as non-substrates of Pgp, whereas those exhibiting B to A/A to B transport ratios ≥2 were considered Pgp substrates. Plasma protein binding was also detd. in vitro via equil. dialysis. Of the 30 compds., 13 were identified to be mouse Pgp substrates, all of which were also human Pgp substrates, demonstrating a good agreement between mouse and human data. In Pgp wild-type mice, the unbound plasma and cerebrospinal fluid concns. of the non-Pgp substrates correlated well, with a regression slope of approx. 1.0. A similar relationship existed for Pgp substrates in Pgp -/- mice. On the other hand, an improved correlation of cerebrospinal fluid and systemic exposures of the Pgp substrates in Pgp wild-type mice was obsd. when the unbound plasma concns. were normalized to the corresponding B to A/A to B transport ratios. These results reinforce the premise that a combined use of unbound plasma drug concns. and in vitro Pgp transport data may be of value for the estn. of central nervous system exposures.(c) Kodaira, H.; Kusuhara, H.; Fujita, T.; Ushiki, J.; Fuse, E.; Sugiyama, Y. Quantitative evaluation of the impact of active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a surrogate J. Pharmacol. Exp. Ther. 2011, 339, 935– 944 DOI: 10.1124/jpet.111.180398[Crossref], [PubMed], [CAS], Google Scholar10chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtVSksbo%253D&md5=36a778b164943b101534146120fc6cdfQuantitative evaluation of the impact of active efflux by P-glycoprotein and breast cancer resistance protein at the blood-brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a surrogateKodaira, Hiroshi; Kusuhara, Hiroyuki; Fujita, Takuya; Ushiki, Junko; Fuse, Eiichi; Sugiyama, YuichiJournal of Pharmacology and Experimental Therapeutics (2011), 339 (3), 935-944CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)This study investigated the impact of the active efflux mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) at the blood-brain barrier (BBB) on the predictability of the unbound brain concn. (Cu,brain) by the concn. in the cerebrospinal fluid (CSF) (Cu,CSF) in rats. Cu,brain is obtained as the product of the total brain concn. and unbound fraction in the brain (fu,brain) detd. in vitro in brain slices. Twenty-five compds., including P-gp and/or Bcrp substrates, were given a const. i.v. infusion, and their plasma, brain, and CSF concns. were detd. P-gp and/or Bcrp substrates, such as verapamil, loperamide, flavopiridol, genistein, quinidine, dantrolene, daidzein, cimetidine, and pefloxacin, showed a higher CSF-to-brain unbound concn. ratio (Kp,uu,CSF/brain) compared with non-P-gp and non-Bcrp substrates. Kp,uu,CSF/brain values of P-gp-specific (quinidine and verapamil) and Bcrp-specific (daidzein and genistein) substrates were significantly decreased in Mdr1a/1b(-/-) and Bcrp(-/-) mice, resp. Furthermore, consistent with the contribution of P-gp and Bcrp to the net efflux at the BBB, Kp,uu,CSF/brain values of the common substrates (flavopiridol and erlotinib) were markedly decreased in Mdr1a/1b(-/-)/Bcrp(-/-) mice, but only moderately or weakly in Mdr1a/1b(-/-) mice and negligibly in Bcrp(-/-) mice. In conclusion, predictability of Cu,brain by Cu,CSF decreases along with the net transport activities by P-gp and Bcrp at the BBB. Cu,CSF of non-P-gp and non-Bcrp substrates can be a reliable surrogate of Cu,brain for lipophilic compds.
- 11Zuccotto, F.; Ardini, E.; Casale, E.; Angiolini, M. Through the “gatekeeper door”: exploiting the active kinase conformation J. Med. Chem. 2010, 53, 2681– 2694 DOI: 10.1021/jm901443h[ACS Full Text], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFGhtb3K&md5=5c6acd058bacfec89b1eff2090f0fe67Through the "Gatekeeper Door": Exploiting the Active Kinase ConformationZuccotto, Fabio; Ardini, Elena; Casale, Elena; Angiolini, MauroJournal of Medicinal Chemistry (2010), 53 (7), 2681-2694CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The development of new kinase inhibitors is still a slow and problematic process. Generally, type I compds. suffer from widespread cross-reactivity among other members of the kinase target family, and intense medicinal chem. optimization programs are required to modulate their activity. Also, fierce competition in the development of scaffolds that could mimic ATP has led to a crowded intellectual property space. The new opportunities opened by the type II compds. created great expectations, as targeting the allosteric site of the ATP pocket offered addnl. opportunities to control selectivity and introduce intellectual property novelty. However, clin. evaluation of these compds. has highlighted how the acquisition of resistance-causing mutations of the kinase target limits their efficacy in cancer treatment.
- 12(a) Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos, A.; Will, Y. Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes ACS Chem. Neurosci. 2010, 1, 420– 434 DOI: 10.1021/cn100007x[ACS Full Text], [CAS], Google Scholar12ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjvVaqtbk%253D&md5=85716be86290fd85e93c6b8d5621683cDefining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety AttributesWager, Travis T.; Chandrasekaran, Ramalakshmi Y.; Hou, Xinjun; Troutman, Matthew D.; Verhoest, Patrick R.; Villalobos, Anabella; Will, YvonneACS Chemical Neuroscience (2010), 1 (6), 420-434CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)As part of our effort to increase survival of drug candidates and to move our medicinal chem. design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) mols. We carried out a thorough anal. of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular, we focused on understanding the relationships between physicochem. properties, in vitro ADME (absorption, distribution, metab., and elimination) attributes, primary pharmacol. binding efficiencies, and in vitro safety data for these two sets of compds. This scholarship provides guidance for the design of CNS mols. in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic.(b) Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties ACS Chem. Neurosci. 2010, 1, 435– 449 DOI: 10.1021/cn100008c[ACS Full Text], [CAS], Google Scholar12bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjvVejtr8%253D&md5=e94998f65a420be6ee4dec4a987cb983Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike PropertiesWager, Travis T.; Hou, Xinjun; Verhoest, Patrick R.; Villalobos, AnabellaACS Chemical Neuroscience (2010), 1 (6), 435-449CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)The interplay among commonly used physicochem. properties in drug design was examd. and utilized to create a prospective design tool focused on the alignment of key druglike attributes. Using a set of six physicochem. parameters ((a) lipophilicity, calcd. partition coeff. (ClogP); (b) calcd. distribution coeff. at pH = 7.4 (ClogD); (c) mol. wt. (MW); (d) topol. polar surface area (TPSA); (e) no. of hydrogen bond donors (HBD); (f) most basic center (pKa)), a druglikeness central nervous system multiparameter optimization (CNS MPO) algorithm was built and applied to a set of marketed CNS drugs (N = 119) and Pfizer CNS candidates (N = 108), as well as to a large diversity set of Pfizer proprietary compds. (N = 11 303). The novel CNS MPO algorithm showed that 74% of marketed CNS drugs displayed a high CNS MPO score (MPO desirability score ≥ 4, using a scale of 0-6), in comparison to 60% of the Pfizer CNS candidates. This anal. suggests that this algorithm could potentially be used to identify compds. with a higher probability of successfully testing hypotheses in the clinic. In addn., a relationship between an increasing CNS MPO score and alignment of key in vitro attributes of drug discovery (favorable permeability, P-glycoprotein (P-gp) efflux, metabolic stability, and safety) was seen in the marketed CNS drug set, the Pfizer candidate set, and the Pfizer proprietary diversity set. The CNS MPO scoring function offers advantages over hard cutoffs or utilization of single parameters to optimize structure-activity relationships (SAR) by expanding medicinal chem. design space through a holistic assessment approach. Based on six physicochem. properties commonly used by medicinal chemists, the CNS MPO function may be used prospectively at the design stage to accelerate the identification of compds. with increased probability of success.
- 13(a)Wu, P.; Nielsen, T. E.; Clausen, M. H. FDA-approved small-molecule kinase inhibitors Trends Pharmacol. Sci. 2015, 36, 422– 439 DOI: 10.1016/j.tips.2015.04.005
For inhibitors approved through 2014:
[Crossref], [PubMed], [CAS], Google Scholar13ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXns1KisLg%253D&md5=a6aa3dbb11e6fe3001fa5fa03a4c950aFDA-approved small-molecule kinase inhibitorsWu, Peng; Nielsen, Thomas E.; Clausen, Mads H.Trends in Pharmacological Sciences (2015), 36 (7), 422-439CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)A review. Kinases have emerged as one of the most intensively pursued targets in current pharmacol. research, esp. for cancer, due to their crit. roles in cellular signaling. To date, the US FDA has approved 28 small-mol. kinase inhibitors, half of which were approved in the past 3 years. While the clin. data of these approved mols. are widely presented and structure-activity relationship (SAR) has been reported for individual mols., an updated review that analyzes all approved mols. and summarizes current achievements and trends in the field has yet to be found. Here we present all approved small-mol. kinase inhibitors with an emphasis on binding mechanism and structural features, summarize current challenges, and discuss future directions in this field.(b)http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm430302.htm (accessed June 12, 2016) .For inhibitors approved in 2015:
- 14Bridges, A. J. Chemical inhibitors of protein kinases Chem. Rev. 2001, 101, 2541– 2572 DOI: 10.1021/cr000250y[ACS Full Text], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXkvVWnt7k%253D&md5=05ee78880cc9dcf485684e05327108dbChemical inhibitors of protein kinasesBridges, Alexander J.Chemical Reviews (Washington, D. C.) (2001), 101 (8), 2541-2571CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review with 258 refs. on development protein kinase inhibitors as potential antitumor agents.
- 15Cole, S.; Bagal, S.; El-Kattan, A.; Fenner, K.; Hay, T.; Kempshall, S.; Lunn, G.; Varma, M.; Stupple, P.; Speed, W. Full efficacy with no CNS side-effects: unachievable panacea or reality? DMPK considerations in design of drugs with limited brain penetration Xenobiotica 2012, 42, 11– 27 DOI: 10.3109/00498254.2011.617847
- 16Huszthy, P. C.; Daphu, I.; Niclou, S. P.; Stieber, D.; Nigro, J. M.; Sakariassen, P.; Miletic, H.; Thorsen, F.; Bjerkvig, R. In vivo models of primary brain tumors: pitfalls and perspectives Neuro-Oncology 2012, 14, 979– 993 DOI: 10.1093/neuonc/nos135
- 17Lee, J.; Kotilarova, S.; Kotliarov, Y.; Li, A.; Su, Q.; Donin, N. M.; Pastorino, S.; Purow, B. W.; Christopher, N.; Zhang, W.; Park, J. K.; Fine, H. A. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines Cancer Cell 2006, 9, 391– 403 DOI: 10.1016/j.ccr.2006.03.030[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XltF2nsLk%253D&md5=d558401715c41e3161463bd475281eaaTumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell linesLee, Jeongwu; Kotliarova, Svetlana; Kotliarov, Yuri; Li, Aiguo; Su, Qin; Donin, Nicholas M.; Pastorino, Sandra; Purow, Benjamin W.; Christopher, Neil; Zhang, Wei; Park, John K.; Fine, Howard A.Cancer Cell (2006), 9 (5), 391-403CODEN: CCAECI; ISSN:1535-6108. (Cell Press)The concept of tumor stem cells (TSCs) provides a new paradigm for understanding tumor biol., although it remains unclear whether TSCs will prove to be a more robust model than traditional cancer cell lines. We demonstrate marked phenotypic and genotypic differences between primary human tumor-derived TSCs and their matched glioma cell lines. Unlike the matched, traditionally grown tumor cell lines, TSCs derived directly from primary glioblastomas harbor extensive similarities to normal neural stem cells and recapitulate the genotype, gene expression patterns, and in vivo biol. of human glioblastomas. These findings suggest that TSCs may be a more reliable model than many commonly utilized cancer cell lines for understanding the biol. of primary human tumors.
- 18Jain, R. K.; di Tomaso, E.; Duda, D. G.; Loeffler, J. S.; Sorensen, A. G.; Batchelor, T. T. Angiogenesis in brain tumors Nat. Rev. Neurosci. 2007, 8, 610– 622 DOI: 10.1038/nrn2175[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnvFKntbk%253D&md5=a7effefbdf690ed77822f1aa2342c91fAngiogenesis in brain tumorsJain, Rakesh K.; di Tomaso, Emmanuelle; Duda, Dan G.; Loeffler, Jay S.; Sorensen, A. Gregory; Batchelor, Tracy T.Nature Reviews Neuroscience (2007), 8 (8), 610-622CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)A review. Despite aggressive surgery, radiotherapy and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumors stimulate the formation of new blood vessels through processes driven primarily by vascular endothelial growth factor (VEGF). However, the resulting vessels are structurally and functionally abnormal, and contribute to a hostile microenvironment (low oxygen tension and high interstitial fluid pressure) that selects for a more malignant phenotype with increased morbidity and mortality. Emerging preclin. and clin. data indicate that anti-VEGF therapies are potentially effective in glioblastoma - the most frequent primary brain tumor - and can transiently normalize tumor vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.
- 19(a) Huang, H.; Held-Feindt, J.; Buhl, R.; Mehdorn, H. M.; Mentlein, R. Expression of VEGF and its receptors in different brain tumors Neurol. Res. 2005, 27, 371– 377 DOI: 10.1179/016164105X39833[Crossref], [PubMed], [CAS], Google Scholar19ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlslemsL8%253D&md5=139fa78457bfdfcbc07d4d03f4ba9cf7Expression of VEGF and its receptors in different brain tumorsHuang, Hongguang; Held-Feindt, Janka; Buhl, Ralf; Mehdorn, Hubertus M.; Mentlein, RolfNeurological Research (2005), 27 (4), 371-377CODEN: NRESDZ; ISSN:0161-6412. (Maney Publishing)Introduction: Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and -2 are considered to play a major in tumor angiogenesis, which is a prerequisite for growth of solid tumors. Glioblastoma multiforme is a prominent example of VEGF-induced tumor vascularization; however, little is known about VEGF and in particular VEGFR expression in other types of brain tumors. Methods: VEGFR mRNA was quantified by real time RT-PCR in 12 different types of brain tumors and compared to VEGF protein content measured by ELISA. VEGF splice variants were detd. by an RT-PCR method. Results: VEGF protein was highest in glioblastoma and metastatic kidney tumors. In all types of tumors the diffusible splice forms VEGF121 and VEGF165 were expressed; VEGF189 was minor in a few tumors. Expression of VEGF receptors did not necessarily correlate with VEGF content. Both were highly expressed in glioblastomas, but in meningiomas VEGF was low and VEGFR high, and in metastatic tumors the reverse. With few exceptions, in particular oligodendrogliomas, VEGFR-1 expression was parallel to VEGFR-2 expression. Interestingly, for the astrocytic gliomas, the expression of VEGFR correlated well to the tumor malignancy, even better than VEGF content. Conclusions: These results show that VEGF and VEGFR expression in various types of brain tumors differ and are not necessarily parallel.(b) Tuettenberg, J.; Friedel, C.; Vajkoczy, P. Angiogenesis in malignant glioma-a target for antitumor therapy? Crit. Rev. Oncol. Hematol. 2006, 59, 181– 193 DOI: 10.1016/j.critrevonc.2006.01.004[Crossref], [PubMed], [CAS], Google Scholar19bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28rhtVGqsw%253D%253D&md5=e2c5eb854b68b1d142b3cfc6ef4ab395Angiogenesis in malignant glioma--a target for antitumor therapy?Tuettenberg J; Friedel C; Vajkoczy PCritical reviews in oncology/hematology (2006), 59 (3), 181-93 ISSN:1040-8428.The prognosis of malignant gliomas is still dismal despite aggressive treatment attempts. Thus, alternative therapy strategies are needed. Malignant gliomas are upon the best vascularized tumors in humans and their proliferation is hallmarked by a distinct proliferative vascular component. Hence it seems to be a logical consequence to apply anti-angiogenic treatment strategies to malignant gliomas. These treatment strategies have shown promising effects in animal models and some experimental clinical studies. This review gives a short introduction into the molecules involved in angiogenesis of malignant gliomas, it provides an overview of the latest experimental developments of glioma angiogenesis inhibition and discusses the results of clinical anti-angiogenic trials in patients with high grade glioma. Additionally the problem of monitoring the treatment success of an anti-angiogenic therapy is addressed.
- 20Barrios, C. H.; Viola, F. S.; Coutinho, L. M.; Paglioli, E. Determination of expression of platelet derived growth factor receptors (PDGFR) in astrocytic tumors J. Clin. Oncol. 2006, 24 (Suppl.) 11518
- 21Wedge, S. R.; Kendrew, J.; Hennequin, L. F.; Valentine, P. J.; Barry, S. J.; Brave, S. R.; Smith, N. R.; James, N. H.; Dukes, M.; Curwen, J. O.; Chester, R.; Jackson, J. A.; Boffey, S. J.; Kilburn, L. L.; Barnett, S.; Richmond, G. H. P.; Wadsworth, P. F.; Walker, M.; Bigley, A. L.; Taylor, S. T.; Cooper, L.; Beck, S.; Jurgensmeier, J. M.; Ogilvie, D. J. AZD2171: A highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer Cancer Res. 2005, 65, 4389– 4400 DOI: 10.1158/0008-5472.CAN-04-4409
- 22Harris, P. A.; Boloor, A.; Cheung, M.; Kumar, R.; Crosby, R. M.; Davis-Ward, R. G.; Epperly, A. H.; Hinkle, K. W.; Hunter, R. N.; Johnson, J. H.; Knick, V. B.; Laudeman, C. P.; Luttrell, D. K.; Mook, R. A.; Nolte, R. T.; Rudolph, S. K.; Szewczyk, J. R.; Truesdale, A. T.; Veal, J. M.; Wang, L.; Stafford, J. A. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor J. Med. Chem. 2008, 51, 4632– 4640 DOI: 10.1021/jm800566m[ACS Full Text], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosVGrtL4%253D&md5=a8737a6e003a3f6002575b4b96712fc9Discovery of 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a Novel and Potent Vascular Endothelial Growth Factor Receptor InhibitorHarris, Philip A.; Boloor, Amogh; Cheung, Mui; Kumar, Rakesh; Crosby, Renae M.; Davis-Ward, Ronda G.; Epperly, Andrea H.; Hinkle, Kevin W.; Hunter, Robert N., III; Johnson, Jennifer H.; Knick, Victoria B.; Laudeman, Christopher P.; Luttrell, Deirdre K.; Mook, Robert A.; Nolte, Robert T.; Rudolph, Sharon K.; Szewczyk, Jerzy R.; Truesdale, Anne T.; Veal, James M.; Wang, Liping; Stafford, Jeffrey A.Journal of Medicinal Chemistry (2008), 51 (15), 4632-4640CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N4-(2,3-dimethyl-2H-indazol-6-yl)-N4-methyl-N2-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clin. development for renal-cell cancer and other solid tumors.
- 23Mulholland, P.; Batchelor, T. T.; Neyns, B. A phase III randomized study comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, with lomustine alone in recurrent glioblastoma patients Proc. ESMO Ann. Oncol. 2010, 21, LBA7
- 24Iwamoto, F. M.; Lamborn, K. R.; Robins, H. I.; Mehta, M. P.; Chang, S. M.; Butowski, N. A.; DeAngelis, L. M.; Abrey, L. E.; Zhang, W.-T.; Prados, M. D.; Fine, H. A. Phase II trial of pazopanib (GW786034), and oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06–02) Neuro Oncol. 2010, 12, 855– 861 DOI: 10.1093/neuonc/noq025[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvFSlt70%253D&md5=8b56b20e22512e58db6e4db2e9f13c6ePhase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02)Iwamoto, Fabio M.; Lamborn, Kathleen R.; Robins, H. Ian; Mehta, Minesh P.; Chang, Susan M.; Butowski, Nicholas A.; DeAngelis, Lisa M.; Abrey, Lauren E.; Zhang, Wei-Ting; Prados, Michael D.; Fine, Howard A.Neuro-Oncology (Cary, NC, United States) (2010), 12 (8), 855-861CODEN: NEURJR; ISSN:1522-8517. (Oxford University Press)The objective of this phase II single-arm study was to evaluate the efficacy and safety of pazopanib, a multi-targeted tyrosine kinase inhibitor, against vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor-α and -β, and c-Kit, in recurrent glioblastoma. Patients with ≤2 relapses and no prior anti-VEGF/VEGFR therapy were treated with pazopanib 800 mg daily on 4-wk cycles without planned interruptions. Brain magnetic resonance imaging and clin. reassessment were made every 8 wk. The primary endpoint was efficacy as measured by 6-mo progression-free survival (PFS6). Thirty-five GBM patients with a median age of 53 years and median Karnofsky performance scale of 90 were accrued. Grade 3/4 toxicities included leukopenia (n = 1), lymphopenia (n = 2), thrombocytopenia (n = 1), ALT elevation (n = 3), AST elevation (n = 1), CNS hemorrhage (n = 1), fatigue (n = 1), and thrombotic/embolic events (n = 3); 8 patients required dose redn. Two patients had a partial radiog. response by std. bidimensional measurements, whereas 9 patients (6 at the 8-wk point and 3 only within the first month of treatment) had decreased contrast enhancement, vasogenic edema, and mass effect but <50% redn. in tumor. The median PFS was 12 wk (95% confidence interval [CI]: 8-14 wk) and only 1 patient had a PFS time ≥6 mo (PFS6 = 3%). Thirty patients (86%) had died and median survival was 35 wk (95% CI: 24-47 wk). Pazopanib was reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR agents. Single-agent pazopanib did not prolong PFS in this patient population but showed in situ biol. activity as demonstrated by radiog. responses. ClinicalTrials.gov identifier: NCT00459381.
- 25Wang, T.; Agarwal, S.; Elmquist, W. F. Brain distribution of cediranib is limited by active efflux at the blood-brain barrier J. Pharmacol. Exp. Ther. 2012, 341, 386– 395 DOI: 10.1124/jpet.111.190488[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xmt1KntLo%253D&md5=e5c34f57afa96152ed0c612561eac08bBrain distribution of cediranib is limited by active efflux at the blood-brain barrierWang, Tianli; Agarwal, Sagar; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2012), 341 (2), 386-395CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Cediranib is an orally active tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor family. Because of its potent antiangiogenic and antitumor activities, cediranib has been evaluated for therapy in glioma, a primary brain tumor. This study investigated the influence of two important efflux transporters at the blood-brain barrier, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), on the delivery of cediranib to the central nervous system. In vitro studies indicated that cediranib is a dual substrate for both P-gp and Bcrp. It is noteworthy that in spite of the in vitro data the in vivo mouse disposition studies conclusively showed that P-gp was the dominant transporter restricting the brain distribution of cediranib. The brain-to-plasma partitioning (AUCbrain/AUCplasma, where AUC is area under the curve) and the steady-state brain-to-plasma concn. ratio of cediranib were approx. 20-fold higher in Mdr1a/b(-/-) and Mdr1a/b(-/-)Bcrp1(-/-) mice compared with wild-type and Bcrp1(-/-) mice. Moreover, there was no significant difference in brain distribution of cediranib between wild-type and Bcrp1(-/-) mice and between Mdr1a/b(-/-) and Mdr1a/b(-/-)Bcrp1(-/-) mice. These results show that, unlike other tyrosine kinase inhibitors that are dual substrates for P-gp and Bcrp, Bcrp does not restrict the distribution of cediranib across the blood-brain barrier. We also show that inhibition of P-gp using specific or nonspecific inhibitors resulted in significantly enhanced delivery of cediranib to the brain. Concurrent administration of cediranib with chem. modulators of efflux transporters can be used as a strategy to enhance delivery and thus efficacy of cediranib in the brain. These findings are clin. relevant to the efficacy of cediranib chemotherapy in glioma.
- 26Minocha, M.; Khurana, V.; Qin, B.; Pal, D.; Mitra, A. K. Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib Int. J. Pharm. 2012, 436, 127– 134 DOI: 10.1016/j.ijpharm.2012.05.038[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht12jsb%252FF&md5=12289c49082640d14eb72d464040df4fEnhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinibMinocha, Mukul; Khurana, Varun; Qin, Bin; Pal, Dhananjay; Mitra, Ashim K.International Journal of Pharmaceutics (Amsterdam, Netherlands) (2012), 436 (1-2), 127-134CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)Primary objective of this investigation was to delineate the differential impact of efflux transporters P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp1/Abcg2) on brain disposition and plasma pharmacokinetics of pazopanib. In addn., this research investigated whether inhibition of these efflux transporters with clin. relevant efflux modulators canertinib or erlotinib could be a viable strategy for improving pazopanib brain delivery. In vitro assays with MDCKII cell monolayers suggested that pazopanib is a high affinity substrate for Bcrp1 and a moderate substrate for P-gp. Co-incubation with specific transport inhibitors restored cell accumulation and completely abolished the directionality of pazopanib flux. Brain and plasma pharmacokinetic studies were conducted in FVB wild type mice in the absence and presence of specific transport inhibitors. Drug levels in plasma and brain were detd. using a validated high performance liq. chromatog. method using vandetanib as an internal std. In vivo studies indicated that specific inhibition of either P-gp (by zosuquidar or LY335979) or Bcrp1 (by Ko143) alone did not significantly alter pazopanib brain accumulation. However, dual P-gp/Bcrp1 inhibition by elacridar (GF120918), significantly enhanced pazopanib brain penetration by ∼5-fold without altering its plasma concns. Thus, even though Bcrp1 showed higher affinity towards pazopanib in vitro, in vivo at the mouse BBB both P-gp and Bcrp1 act in concert to limit brain accumulation of pazopanib. Furthermore, erlotinib and canertinib as clin. relevant efflux modulators efficiently abrogated directionality in pazopanib efflux in vitro and their co-administration resulted in 2-2.5-fold increase in pazopanib brain accumulation in vivo. Further pre-clin. and clin. investigations are warranted as erlotinib or canertinib may have a synergistic pharmacol. effect in addn. to their primary role of pazopanib efflux modulation as a combination regimen for the treatment of recurrent brain tumors.
- 27Atkins, M.; Jones, C. A.; Kirkpatrick, P. Sunitinib maleate Nat. Rev. Drug Discovery 2006, 5, 279– 280 DOI: 10.1038/nrd2012
- 28Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R. A.; Schwartz, B.; Simantov, R.; Kelley, S. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer Nat. Rev. Drug Discovery 2006, 5, 835– 844 DOI: 10.1038/nrd2130[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVajsbbM&md5=490d4995170f3a7270ae9bbdd24b12e5Discovery and development of sorafenib: a multikinase inhibitor for treating cancerWilhelm, Scott; Carter, Christopher; Lynch, Mark; Lowinger, Timothy; Dumas, Jacques; Smith, Roger A.; Schwartz, Brian; Simantov, Ronit; Kelley, SusanNature Reviews Drug Discovery (2006), 5 (10), 835-844CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Since the mol. revolution of the 1980s, knowledge of the etiol. of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, the authors describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumor signaling and the tumor vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) - from initial screening for a lead compd. to FDA approval for the treatment of advanced renal cell carcinoma in Dec. 2005 - was completed in just 11 years, with approval being received ∼5 years after the initiation of the first Phase I trial.
- 29Roth, G. J.; Binder, R.; Colbatzky, F.; Dallinger, C.; Schlenker-Herceq, R.; Hilberg, F.; Wollin, S. L.; Kaiser, R. Nintedanib: from discovery to the clinic J. Med. Chem. 2015, 58, 1053– 1063 DOI: 10.1021/jm501562a[ACS Full Text], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVegurnO&md5=dd1bc3c81b83b21cfb9b0d3da7f7b55dNintedanib: From Discovery to the ClinicRoth, Gerald J.; Binder, Rudolf; Colbatzky, Florian; Dallinger, Claudia; Schlenker-Herceg, Rozsa; Hilberg, Frank; Wollin, Stefan-Lutz; Kaiser, RolfJournal of Medicinal Chemistry (2015), 58 (3), 1053-1063CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Nintedanib (BIBF1120) is a potent, oral, small-mol. tyrosine kinase inhibitor, also known as a triple angiokinase inhibitor, inhibiting three major signaling pathways involved in angiogenesis. Nintedanib targets proangiogenic and pro-fibrotic pathways mediated by the VEGFR family, the fibroblast growth factor receptor (FGFR) family, the platelet-derived growth factor receptor (PDGFR) family, as well as Src and Flt-3 kinases. The compd. was identified during a lead optimization program for small-mol. inhibitors of angiogenesis and has since undergone extensive clin. investigation for the treatment of various solid tumors, and in patients with the debilitating lung disease idiopathic pulmonary fibrosis (IPF). Recent clin. evidence from phase III studies has shown that nintedanib has significant efficacy in the treatment of NSCLC, ovarian cancer, and IPF. This review article provides a comprehensive summary of the preclin. and clin. research and development of nintedanib from the initial drug discovery process to the latest available clin. trial data.
- 30Nakamura, K.; Taguchi, E.; Miura, T.; Yamamoto, A.; Takahashi, K.; Bichat, F.; Guilbaud, N.; Hasegawa, K.; Kubo, K.; Fujiwara, Y.; Suzuki, R.; Kubo, K.; Shibuya, M.; Isae, T. KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties Cancer Res. 2006, 66, 9134– 9142 DOI: 10.1158/0008-5472.CAN-05-4290
- 31Renhowe, P. A.; Pecchi, S.; Shafer, C. M.; Machajewski, T. D.; Jazan, E. M.; Taylor, C.; Antonios-McCrea, W.; McBride, C. M.; Frazier, K.; Wiesmann, M.; Lapointe, G. R.; Feucht, P. H.; Warne, R. L.; Heise, C. C.; Menezes, D.; Aardalen, K.; Ye, H.; He, M.; Le, V.; Vora, J.; Jansen, J. M.; Wernette-Hammond, M. E.; Harris, A. L. Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors J. Med. Chem. 2009, 52, 278– 292 DOI: 10.1021/jm800790t[ACS Full Text], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnt1Sl&md5=f20f564bb7dacb5a450a29dae9e04b50Design, Structure-Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase InhibitorsRenhowe, Paul A.; Pecchi, Sabina; Shafer, Cynthia M.; Machajewski, Timothy D.; Jazan, Elisa M.; Taylor, Clarke; Antonios-McCrea, William; McBride, Christopher M.; Frazier, Kelly; Wiesmann, Marion; Lapointe, Gena R.; Feucht, Paul H.; Warne, Robert L.; Heise, Carla C.; Menezes, Daniel; Aardalen, Kimberly; Ye, Helen; He, Molly; Le, Vincent; Vora, Jayesh; Jansen, Johanna M.; Wernette-Hammond, Mary Ellen; Harris, Alex L.Journal of Medicinal Chemistry (2009), 52 (2), 278-292CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncol. research over the last several years. Many potent small mol. inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compds. that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clin. efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogs as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compds. in this class, such as TKI258 (I), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRβ with IC50 values <0.1 μM. On the basis of its favorable in vitro and in vivo properties, compd. I was selected for clin. evaluation and is currently in phase I clin. trials.
- 32(a) Balana, C.; Gil, M. J.; Reynes, G.; Capellades, J.; Ribalta, T.; Gallego, O.; Segura, P. P.; Verger, E. A phase II multicentric study of sunitinib administered as upfront therapy in glioblastoma: a study by the GEINO group J. Clin. Oncol. 2012, 30, 2045(b) Kreisl, T. N.; Smith, P.; Sul, J.; Salgado, C.; Iwamoto, F. M.; Shih, J. H.; Fine, H. A. Continuous daily sunitinib for recurrent glioblastoma J. Neuro-Oncol. 2013, 111, 41– 48 DOI: 10.1007/s11060-012-0988-z[Crossref], [PubMed], [CAS], Google Scholar32bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvFSgtLnN&md5=74c5a15570b521164f7813043d4f3ee8Continuous daily sunitinib for recurrent glioblastomaKreisl, Teri Nguyen; Smith, Perry; Sul, Joohee; Salgado, Carlos; Iwamoto, Fabio M.; Shih, Joanna H.; Fine, Howard A.Journal of Neuro-Oncology (2013), 111 (1), 41-48CODEN: JNODD2; ISSN:0167-594X. (Springer)Bevacizumab (BEV) has become a mainstay of treating recurrent glioblastoma, but eventual tumor resistance is expected. Targeting multiple growth-assocd. signaling pathways may result in more effective treatment than targeting VEGF alone. Patients with recurrent glioblastoma were stratified by prior BEV exposure and treated with sunitinib 37.5 mg daily in this phase II study. Response evaluations were performed at baseline and at the end of every 4 wk cycle. Six-month progression-free survival (PFS6) was the primary endpoint for both arms of the study. Secondary endpoints included health related quality of life measures and FDG-PET correlatives with patient outcomes. Sixty-three patients were accrued to this study; thirty-two were BEV-naive, 31 were BEV-resistant. PFS6 was 10.4 % [95 % CI 3.2-33.8] in the BEV-naive cohort and 0 % in the BEV-resistant cohort. Median overall survival was 9.4 mo [95 % CI 6.15-21.90] in the BEV-naive cohort and 4.37 mo [95 % CI 3.02-6.21] in the BEV-resistant cohort. 3/29 patients (10 %) of the BEV-naive, and 0/27 BEV-resistant patients achieved radiog. response. Thrombocytopenia, leukopenia, and neutropenia were the most common drug-assocd. adverse events and occurred with higher frequency than expected. Sunitinib treatment in BEV-naive patients did not appear to affect outcomes with subsequent BEV therapy. Continuous daily sunitinib did not prolong progression-free survival in BEV-naive nor BEV-resistant patients with recurrent glioblastoma.(c) Reardon, D. A.; Vredenburgh, J. J.; Coan, A.; Desjardins, A.; Peters, K. B.; Gururangan, S.; Sathornsumetee, S.; Rich, J. N.; Herndon, J. E.; Friedman, H. S. Phase I study of sunitinib and irinotecan for patients with recurrent malignant glioma J. Neuro-Oncol. 2011, 105, 621– 627 DOI: 10.1007/s11060-011-0631-4[Crossref], [PubMed], [CAS], Google Scholar32chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVyrtLfK&md5=a0f07732c407a80b4f742b5b1da09622Phase I study of sunitinib and irinotecan for patients with recurrent malignant gliomaReardon, David A.; Vredenburgh, James J.; Coan, April; Desjardins, Annick; Peters, Katherine B.; Gururangan, Sridharan; Sathornsumetee, Sith; Rich, Jeremy N.; Herndon, James E.; Friedman, Henry S.Journal of Neuro-Oncology (2011), 105 (3), 621-627CODEN: JNODD2; ISSN:0167-594X. (Springer)We detd. the max. tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, sunitinib, when administered with irinotecan among recurrent malignant glioma (MG) patients. For each 42-day cycle, sunitinib was administered once a day for four consecutive weeks followed by a 2 wk rest. Irinotecan was administered i.v. every other week. Each agent was alternatively escalated among cohorts of 3-6 patients enrolled at each dose level. Patients on CYP3A-inducing anti-epileptic drugs were not eligible. Twenty-five patients with recurrent MG were enrolled, including 15 (60%) with glioblastoma (GBM) and 10 (40%) with grade 3 MG. Five patients progressed previously on bevacizumab and two had received prior VEGFR tyrosine kinase inhibitor therapy. The MTD was 50 mg of sunitinib combined with 75 mg/m2 of irinotecan. DLT were primarily hematol. and included grade 4 neutropenia in 3 patients and one patient with grade 4 thrombocytopenia. Non-hematol. DLT included grade 3 mucositis (n = 1) and grade 3 dehydration (n = 1). Progression-free survival (PFS)-6 was 24% and only one patient achieved a radiog. response. The combination of sunitinib and irinotecan was assocd. with moderate toxicity and limited anti-tumor activity. Further studies with this regimen using the dosing schedules evaluated in this study are not warranted.
- 33(a) Lee, E. Q.; Kuhn, J.; Lamborn, K. R.; Abrey, L.; DeAngelis, L. M.; Lieberman, F.; Robins, H. I.; Chang, S. M.; Yung, W. K. A.; Drappatz, J.; Mehta, M. P.; Levin, V. A.; Aldape, K.; Dancey, J. E.; Wright, J. J.; Prados, M. D.; Cloughesy, T. F.; Gilbert, M. R.; Wen, P. Y. Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02 Neuro-Oncology 2012, 14, 1511– 1518 DOI: 10.1093/neuonc/nos264(b) Hainsworth, J. D.; Ervin, T.; Friedman, E.; Priego, V.; Murphy, P. B.; Clark, B. L.; Lamar, R. E. Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first-line treatment of patients with glioblastoma multiforme Cancer 2010, 116, 3663– 3669 DOI: 10.1002/cncr.25275
- 34Muhic, A.; Poulsen, H. S.; Sorensen, M.; Grunnet, K.; Lassen, U. Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme J. Neuro-Oncol. 2013, 111, 205– 212 DOI: 10.1007/s11060-012-1009-y[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpt1Kiuw%253D%253D&md5=e380c9967f338d6cfd73d383d5132393Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiformeMuhic, Aida; Poulsen, Hans Skovgaard; Sorensen, Morten; Grunnet, Kirsten; Lassen, UlrikJournal of Neuro-Oncology (2013), 111 (2), 205-212CODEN: JNODD2; ISSN:0167-594X. (Springer)Nintedanib (BIBF 1120) is a small, orally available, triple angiokinase inhibitor in phase III development (various indications) that targets VEGFR 1-3, FGFR 1-3, and PDGFR-α/β. This open-label, uncontrolled, phase II study assessed the efficacy and safety of nintedanib in patients with recurrent glioblastoma multiforme (GBM) who had previously failed radiotherapy plus temozolomide as first-line therapy (STUPP), or the same regimen with subsequent bevacizumab-based therapy as second-line treatment (BEV). Patients with a performance status of 0-1, histol. proven GBM, and measurable disease (by RANO) were enrolled. Nintedanib was given orally at a dose of 200 mg twice daily (bid), with magnetic resonance imaging undertaken every 8 wk. The primary endpoint was objective response rate. The study was stopped prematurely following a preplanned futility anal. after inclusion of 13 patients in the STUPP arm and 12 in the BEV arm. Best response was stable disease (SD) in three patients (12 %); all other patients progressed within the first four 28-day cycles. One patient in the BEV arm has had SD for 17+ months. Median progression-free survival was 1 mo and median overall survival was 6 mo. Nintedanib had an acceptable safety profile, with no CTCAE grade 3-4 adverse events. Common adverse events were CTCAE grade 1-2 fatigue, loss of appetite, diarrhea, and nausea. Single-agent nintedanib (200 mg bid) demonstrated limited, but clin. non-relevant antitumor activity in patients with recurrent GBM who had failed 1-2 prior lines of therapy.
- 35Cai, X.; Chandra, V.; Ou, Y.; Emblem, K. E.; Muzikansky, A.; Evans, J.; Kalpathy-Cramer, J.; Dietrich, J.; Chi, A. S.; Wen, P. Y.; Rosen, B. R.; Batchelor, T.; Gerstner, E. R.; Martinos, A. A. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma J. Clin. Oncol. 2015, 33 (Suppl.) 2025
- 36Ahluwalia, M. S.; Papadantonakis, N.; Venur, V. A.; Schilero, C.; Peereboom, D. M.; Stevens, G.; Rosenfeld, S.; Vogelbaum, M. A.; Elson, P.; Nixon, A. B.; McCrae, K. Phase II trial of dovitinib in recurrent glioblastoma J. Clin. Oncol. 2015, 33 (Suppl.) 2050
- 37(a) Oberoi, R. K.; Mittapalli, R. K.; Fisher, J.; Elmquist, W. F. Sunitinib LC-MS/MS assay in mouse plasma and brain tissue: application in CNS distribution studies Chromatographia 2013, 76, 1657– 1665 DOI: 10.1007/s10337-013-2528-1(b) Tang, S. C.; Lagas, J. S.; Lankheet, N. A. G.; Poller, B.; Hillebrand, M. J.; Rosing, H.; Bejinen, J. H.; Schinkel, A. H. Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration Int. J. Cancer 2012, 130, 223– 233 DOI: 10.1002/ijc.26000[Crossref], [PubMed], [CAS], Google Scholar37bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlOmsrjP&md5=47fee810fd84296c9b1598fd8e80acf7Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministrationTang, Seng Chuan; Lagas, Jurjen S.; Lankheet, Nienke A. G.; Poller, Birk; Hillebrand, Michel J.; Rosing, Hilde; Beijnen, Jos H.; Schinkel, Alfred H.International Journal of Cancer (2012), 130 (1), 223-233CODEN: IJCNAW; ISSN:0020-7136. (John Wiley & Sons, Inc.)Sunitinib is an orally active, multitargeted tyrosine kinase inhibitor which has been used for the treatment of metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. We aimed to investigate the in vivo roles of the ATP-binding cassette drug efflux transporters ABCB1 and ABCG2 in plasma pharmacokinetics and brain accumulation of oral sunitinib, and the feasibility of improving sunitinib kinetics using oral coadministration of the dual ABCB1/ABCG2 inhibitor elacridar. We used in vitro transport assays and Abcb1a/1b-/-, Abcg2-/- and Abcb1a/1b/Abcg2-/- mice to study the roles of ABCB1 and ABCG2 in sunitinib disposition. In vitro, sunitinib was a good substrate of murine (mu)ABCG2 and a moderate substrate of human (hu)ABCB1 and huABCG2. In vivo, the systemic exposure of sunitinib after oral dosing (10 mg kg-1) was unchanged when muABCB1 and/or muABCG2 were absent. Brain accumulation of sunitinib was markedly (23-fold) increased in Abcb1a/b/Abcg2-/- mice, but only slightly (2.3-fold) in Abcb1a/b-/- mice, and not in Abcg2-/- mice. Importantly, a clin. realistic coadministration of oral elacridar and oral sunitinib to wild-type mice resulted in markedly increased sunitinib brain accumulation, equaling levels in Abcb1a/1b/Abcg2-/- mice. This indicates complete inhibition of the blood-brain barrier (BBB) transporters. High-dose i.v. sunitinib could sat. BBB muABCG2, but not muABCB1A, illustrating a dose-dependent relative impact of the BBB transporters. Brain accumulation of sunitinib is effectively restricted by both muABCB1 and muABCG2 activity. Complete inhibition of both transporters, leading to markedly increased brain accumulation of sunitinib, is feasible and safe with a clin. realistic oral elacridar/sunitinib coadministration.
- 38(a) Lagas, J. S.; van Waterschoot, R. A. B.; Sparidans, R. W.; Wagenaar, E.; Beijnen, J. H.; Schinkel, A. H. Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation Mol. Cancer Ther. 2010, 9, 319– 326 DOI: 10.1158/1535-7163.MCT-09-0663[Crossref], [PubMed], [CAS], Google Scholar38ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhslektLo%253D&md5=f7d2e4cb7f706f63320bddc603103462Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain AccumulationLagas, Jurjen S.; van Waterschoot, Robert A. B.; Sparidans, Rolf W.; Wagenaar, Els; Beijnen, Jos H.; Schinkel, Alfred H.Molecular Cancer Therapeutics (2010), 9 (2), 319-326CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Sorafenib is a second-generation, orally active multikinase inhibitor that is approved for the treatment of patients with advanced renal cell carcinoma and patients with unresectable hepatocellular carcinoma. The authors studied active transport of sorafenib in MDCK-II cells expressing human P-glycoprotein (P-gp/ABCB1) or ABCG2 (breast cancer resistance protein) or murine Abcg2. Sorafenib was moderately transported by P-gp and more efficiently by ABCG2 and Abcg2. Because sorafenib is taken orally, the authors orally administered sorafenib to wild-type, Abcb1a/1b-/-, Abcg2-/-, and Abcb1a/1b;Abcg2-/- mice, completely lacking functional Abcb1a/1b, Abcg2, or both, resp., and the authors studied plasma pharmacokinetics and brain accumulation. The systemic exposure on oral administration was not different among all strains. However, brain accumulation was 4.3-fold increased in Abcg2-/- mice and 9.3-fold increased in Abcb1a/1b;Abcg2-/- mice. Moreover, when wild-type mice were treated with sorafenib in combination with the dual P-gp and ABCG2 inhibitor elacridar, brain accumulation was similar to that obsd. for Abcb1a/1b;Abcg2-/- mice. These results show that the brain accumulation of sorafenib is primarily restricted by ABCG2. This contrasts with previous studies using shared ABCG2 and P-gp substrates, which all suggested that P-gp dominates at the blood-brain barrier, and that an effect of ABCG2 is only evident when both transporters are absent. Interestingly, for sorafenib, it is the other way around, i.e., ABCG2, and not P-gp, plays the dominant role in restricting its brain accumulation. Clin., the authors' findings may be relevant for the treatment of renal cell carcinoma patients with central nervous system relapses, as a dual ABCG2 and P-gp inhibitor might improve the central nervous system entry and thereby the therapeutic efficacy of sorafenib. Mol Cancer Ther; 9(2); 319-26.(b) Agarwal, S.; Sane, R.; Ohlfest, J. R.; Elmquist, W. F. The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain J. Pharmacol. Exp. Ther. 2011, 336, 223– 233 DOI: 10.1124/jpet.110.175034[Crossref], [PubMed], [CAS], Google Scholar38bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXls1eqtg%253D%253D&md5=9d8057bda22f1dc0ab81aea9fb7906a0The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brainAgarwal, Sagar; Sane, Ramola; Ohlfest, John R.; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2011), 336 (1), 223-233CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)ATP-binding cassette transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) have been shown to work in concert to restrict brain penetration of several tyrosine kinase inhibitors. It has been reported that P-gp is dominant in limiting transport of many dual P-gp/BCRP substrates across the blood-brain barrier (BBB). This study investigated the influence of P-gp and BCRP on the central nervous system (CNS) penetration of sorafenib, a multitargeted tyrosine kinase inhibitor currently being evaluated in clin. trials for glioma. In vitro studies showed that BCRP has a high affinity for sorafenib. Sorafenib inhibited P-gp, but did not seem to be a P-gp substrate in vitro. CNS distribution studies showed that transport of sorafenib to the brain was restricted because of active efflux at the BBB. The brain-to-plasma equil.-distribution coeff. (area under the concn.-time profiles for plasma/area under the concn.-time profiles for brain) was 0.06 in wild-type mice. Steady-state brain-to-plasma concn. ratio of sorafenib was approx. 0.36 ± 0.056 in the Bcrp1(-/-) mice, 0.11 ± 0.021 in the Mdr1a/b(-/-) mice, and 0.91 ± 0.29 in the Mdr1a/b(-/-)Bcrp1(-/-) mice compared with 0.094 ± 0.007 in the wild-type mice. Sorafenib brain-to-plasma ratios increased on coadministration of the dual P-gp/BCRP inhibitor elacridar such that the ratio in wild-type mice (0.76 ± 0.24), Bcrp1(-/-) mice (1.03 ± 0.33), Mdr1a/b(-/-) mice (1.3 ± 0.29), and Mdr1a/b(-/-)Bcrp1(-/-) mice (0.73 ± 0.35) were not significantly different. This study shows that BCRP and P-gp together restrict the brain distribution of sorafenib with BCRP playing a dominant role in the efflux of sorafenib at the BBB. These findings are clin. relevant to chemotherapy in glioma if restricted drug delivery to the invasive tumor cells results in decreased efficacy.(c) Asakawa, C.; Ogawa, M.; Kumata, K.; Fujinaga, M.; Kato, K.; Yamasaki, T.; Yui, J.; Kawamura, K.; Hatori, A.; Fukumura, T.; Zhang, M.-R. [11C]Sorafenib: radiosynthesis and preliminary PET study of brain uptake in P-gp/Bcrp knockout mice Bioorg. Med. Chem. Lett. 2011, 21, 2220– 2223 DOI: 10.1016/j.bmcl.2011.03.002
- 39Hussar, D. A.; Jeon, M. M. Naloxegol oxalate, pirfenidone, and nintedanib J. Am. Pharm. Assoc. 2015, 55, 461– 463 DOI: 10.1331/JAPhA.2015.15523
- 40Helgason, H. H.; Mallo, H. A.; Droogendijk, H.; Haanen, J. G.; van der Veldt, A. A. M.; van den Eertwegh, A. J.; Boven, E. Brain metastases in patients with renal cell cancer receiving new targeted treatment J. Clin. Oncol. 2008, 26, 152– 154 DOI: 10.1200/JCO.2007.13.5814[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c%252Fgt1ertg%253D%253D&md5=709cd92719a0dcb5849966d939d795b0Brain metastases in patients with renal cell cancer receiving new targeted treatmentHelgason Helgi H; Mallo Henk A; Droogendijk Helga; Haanen John G; van der Veldt Astrid A M; van den Eertwegh Alfonsus J; Boven EpieJournal of clinical oncology : official journal of the American Society of Clinical Oncology (2008), 26 (1), 152-4 ISSN:.There is no expanded citation for this reference.
- 41Wilhelm, S. M.; Dumas, J.; Adnane, L.; Lynch, M.; Carter, C. A.; Schutz, G.; Thierauch, K. H.; Zopf, D. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity Int. J. Cancer 2011, 129, 245– 255 DOI: 10.1002/ijc.25864[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltFGlu7c%253D&md5=13eee29ef1f1f03fd1ed311ea613f566Regorafenib (BAY 73-4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activityWilhelm, Scott M.; Dumas, Jacques; Adnane, Lila; Lynch, Mark; Carter, Christopher A.; Schuetz, Gunnar; Thierauch, Karl-Heinz; Zopf, DieterInternational Journal of Cancer (2011), 129 (1), 245-255CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)Angiogenesis, a crit. driver of tumor development, is controlled by interconnected signaling pathways. Vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with Ig and epidermal growth factor homol. domain 2 play crucial roles in the biol. of normal and tumor vasculature. Regorafenib (BAY 73-4506), a novel oral multikinase inhibitor, potently inhibits these endothelial cell kinases in biochem. and cellular kinase phosphorylation assays. Furthermore, regorafenib inhibits addnl. angiogenic kinases (VEGFR1/3, platelet-derived growth factor receptor-β and fibroblast growth factor receptor 1) and the mutant oncogenic kinases KIT, RET and B-RAF. The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast-enhanced magnetic resonance imaging. Regorafenib administered once orally at 10 mg/kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts. In a daily (qd)×4 dosing study, the pharmacodynamic effects persisted for 48 h after the last dosing and correlated with tumor growth inhibition (TGI). A significant redn. in tumor microvessel area was obsd. in a human colorectal xenograft after qd×5 dosing at 10 and 30 mg/kg. Regorafenib exhibited potent dose-dependent TGI in various preclin. human xenograft models in mice, with tumor shrinkages obsd. in breast MDA-MB-231 and renal 786-O carcinoma models. Pharmacodynamic analyses of the breast model revealed strong redn. in staining of proliferation marker Ki-67 and phosphorylated extracellular regulated kinases 1/2. These data demonstrate that regorafenib is a well-tolerated, orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies.
- 42EU Clinical Trials Register. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-003722-41 (accessed June 9, 2016) .
- 43Kort, A.; Durmus, S.; Sparidans, R. W.; Wagenaar, E.; Beijnen, J. H.; Schinkel, A. H. Brain and testis accumulation of regorafenib is restricted by breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) Pharm. Res. 2015, 32, 2205– 2216 DOI: 10.1007/s11095-014-1609-7
- 44Yang, J. J.; Milton, M. N.; Liao, M.; Liu, N.; Wu, J. T.; Gan, L.; Balani, S. K.; Lee, F. W.; Prakash, S.; Xia, C. Q. P-glycloprotein and breast cancer resistance protein affect disposition of tandutinib, a tyrosine kinase inhibitor Drug Metab. Lett. 2010, 4, 202– 212 DOI: 10.2174/187231210792928279[Crossref], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFCit73I&md5=33eda66652a724416094b4d1823ec424P-glycoprotein and breast cancer resistance protein affect disposition of tandutinib, a tyrosine kinase inhibitorYang, Johnny J.; Milton, Mark N.; Yu, Shaoxia; Liao, Mingxiang; Liu, Ning; Wu, Jing-Tao; Gan, Liang-Shang; Balani, Suresh K.; Lee, Frank W.; Prakash, Shimoga; Xia, Cindy Q.Drug Metabolism Letters (2010), 4 (4), 202-212CODEN: DMLRBM; ISSN:1872-3128. (Bentham Science Publishers Ltd.)Tandutinib is a tyrosine kinase inhibitor under investigation for the treatment of solid and hematol. tumors. We evaluated efflux transporter substrate specificity of tandutinib in Caco-2 cells, and the role of efflux transporters in the disposition of tandutinib in rats and efflux transporter knock-out mice. These studies demonstrated that tandutinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in Caco-2 cells. In rats, administration of GF120918, before treatment with tandutinib orally resulted in approx. a seven-fold increase in the mean plasma area under the concn.-vs.-time curve (AUC) compared to the vehicle control group. In mice, after i.v. administration of tandutinib, the mean plasma AUC values in the Bcrp1(-/-) mice and Mdr1a/b(-/-) mice was 1.53- and 1.20-fold greater than that of the wild type (WT) mice, resp. After oral administration, the drug exposure in Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)/Bcrp1(-/-) mice was higher than in the WT mice. The brain to plasma exposure ratio (B/P) of tandutinib in Mdr1a/b(-/-) mice increased by 2- to 3-fold over that in the WT mice. There was a 13-fold increase in B/P in Mdr1a/b(-/-)/Bcrp1(-/-) mice. This finding illustrates that P-gp and Bcrp play a role in oral absorption, systemic clearance, and brain penetration of tandutinib in the rodents. P-gp affected oral absorption and brain penetration of tandutinib to a greater extent than Bcrp, but Bcrp contribution to systemic clearance of tandutinib was greater than P-gp. Thus, co-administration of efflux pump inhibitors may be a useful strategy to enhance tandutinib absorption and brain penetration clin.
- 45Supko, J. G.; Grossman, S. A.; Peereboom, D. M.; Chowdhary, S.; Lesser, G. J.; Nabors, L. B.; Mikkelsen, T.; Desideri, S.; Batchelor, T. T. Feasibility and phase I trial of tandutinib in patients with recurrent glioblastoma J. Clin. Oncol. 2009, 27 (15s) 2039
- 46Lu, L.; Saha, D.; Martuza, R. L.; Rabkin, S. D.; Wakimoto, H. Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastoma J. Neuro-Oncol. 2015, 121, 91– 100 DOI: 10.1007/s11060-014-1612-1[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFGhu7zK&md5=0d0dfdb9ee7a3adce51badb64a322448Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastomaLu, Lei; Saha, Dipongkor; Martuza, Robert L.; Rabkin, Samuel D.; Wakimoto, HiroakiJournal of Neuro-Oncology (2015), 121 (1), 91-100CODEN: JNODD2; ISSN:0167-594X. (Springer)Anti-angiogenic therapy is a promising therapeutic strategy for the highly vascular and malignant brain tumor, glioblastoma (GBM), although current clin. trials have failed to demonstrate an extension in overall survival. The small mol. tyrosine kinase inhibitor axitinib that targets vascular endothelial growth factor receptor, potently inhibits angiogenesis and has single-agent clin. activity in non-small cell lung, thyroid, and advanced renal cell cancer. Here we show that axitinib exerts direct cytotoxic activity against a no. of patient-derived GBM stem cell (GSCs) and an endothelial cell line, and inhibits endothelial tube formation in vitro. Axitinib treatment of mice bearing hypervascular intracranial tumors generated from human U87 glioma cells, MGG4 GSCs and mouse 005 GSCs significantly extended survival that was assocd. with decreases in tumor-assocd. vascularity. We thus show for the first time the anti-angiogenic effect and survival prolongation provided by systemic single agent treatment with axitinib in preclin. orthotopic GBM models including clin. relevant GSC models. These results support further investigation of axitinib as an anti-angiogenic agent for GBM.
- 47Zakharia, Y.; Zakharia, K.; Rixe, O. Axitinib: from preclinical development to future clinical perspectives in renal cell carcinoma Expert Opin. Drug Discovery 2015, 10, 925– 935 DOI: 10.1517/17460441.2015.1045411
- 48Neyns, B.; Duerinck, J.; Du Four, S.; Bouttens, F.; Verschaeve, V.; Everaert, H.; Van Binst, A. Randomized phase II study of axitinib versus standard of care in patients with recurrent glioblastoma J. Clin. Oncol. 2014, 32 (Suppl.) 2018
- 49Poller, B.; Iusuf, D.; Sparidans, R. W.; Wagenaar, E.; Beijnen, J. H.; Schinkel, A. H. Differential impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on axitinib brain accumulation and oral plasma pharmacokinetics Drug Metab. Dispos. 2011, 39, 729– 735 DOI: 10.1124/dmd.110.037317
- 50Sim, M. W.; Cohen, M. S. The discovery and development of vandetanib for the treatment of thyroid cancer Expert Opin. Drug Discovery 2014, 9, 105– 114 DOI: 10.1517/17460441.2014.866942
- 51Matsui, J.; Yamamoto, Y.; Funahashi, Y.; Tsuruoka, A.; Watanabe, T.; Wakabayashi, T.; Uenaka, T.; Asada, M. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition Int. J. Cancer 2008, 122, 664– 671 DOI: 10.1002/ijc.23131[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2sjhvVGnsA%253D%253D&md5=cfa467e773fd98d6f95b0dded62d31efE7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibitionMatsui Junji; Yamamoto Yuji; Funahashi Yasuhiro; Tsuruoka Akihiko; Watanabe Tatsuo; Wakabayashi Toshiaki; Uenaka Toshimitsu; Asada MakotoInternational journal of cancer (2008), 122 (3), 664-71 ISSN:.E7080 is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. In this study, we show the inhibitory activity of E7080 against SCF-induced angiogenesis in vitro and tumor growth of SCF-producing human small cell lung carcinoma H146 cells in vivo. E7080 inhibits SCF-driven tube formation of HUVEC, which express SCF receptor, KIT at the IC(50) value of 5.2 nM and it was almost identical for VEGF-driven one (IC(50) = 5.1 nM). To assess the role of SCF/KIT signaling in tumor angiogenesis, we evaluated the effect of imatinib, a selective KIT kinase inhibitor, on tumor growth of H146 cells in nude mice. Imatinib did not show the potent antitumor activity in vitro (IC(50) = 2,200 nM), because H146 cells did not express KIT. However, oral administration of imatinib at 160 mg/kg clearly slowed tumor growth of H146 cells in nude mice, accompanied by decreased microvessel density. Oral administration of E7080 inhibited tumor growth of H146 cells at doses of 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg. While anti-VEGF antibody also slowed tumor growth, it did not cause tumor regression. These results indicate that KIT signaling has a role in tumor angiogenesis of SCF-producing H146 cells, and E7080 causes regression of H146 tumors as a result of antiangiogenic activity mediated by inhibition of both KIT and VEGF receptor signaling. E7080 may provide therapeutic benefits in the treatment of SCF-producing tumors.
- 52(a) Drappatz, J.; Norden, A. D.; Wong, E. T.; Doherty, L. M.; LaFrankie, D. C.; Ciampa, A.; Kesari, S.; Sceppa, C.; Gerard, M.; Phan, P.; Schiff, D.; Batchelor, T. T.; Ligon, K. L.; Young, G.; Muzikansky, A.; Weiss, S. E.; Wen, P. Y. Phase I study of vandetanib with radiotherapy and temozolomide for newly diagnosed glioblastoma Int. J. Radiat. Oncol., Biol., Phys. 2010, 78, 85– 90 DOI: 10.1016/j.ijrobp.2009.07.1741[Crossref], [PubMed], [CAS], Google Scholar52ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVaqtr7E&md5=c0f43c60f1714769257fce187b91de3fPhase I Study of Vandetanib With Radiotherapy and Temozolomide for Newly Diagnosed GlioblastomaDrappatz, Jan; Norden, Andrew D.; Wong, Eric T.; Doherty, Lisa M.; LaFrankie, Debra C.; Ciampa, Abigail; Kesari, Santosh; Sceppa, Christine; Gerard, Mary; Phan, Phuong; Schiff, David; Batchelor, Tracy T.; Ligon, Keith L.; Young, Geoffrey; Muzikansky, Alona; Weiss, Stephanie E.; Wen, Patrick Y.International Journal of Radiation Oncology, Biology, Physics (2010), 78 (1), 85-90CODEN: IOBPD3; ISSN:0360-3016. (Elsevier Inc.)Purpose: Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addn., epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ). Methods and Materials: A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvant TMZ, using a std. "3 + 3" dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 wk of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of ≥60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs. Results: Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 wk, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities obsd., establishing this dose as the maximal tolerated dose combined with TMZ and RT. Conclusion: Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway.(b) Chheda, M. G.; Wen, P. Y.; Hochberg, F. H.; Chi, A. S.; Drappatz, J.; Eichler, A. F.; Yang, D.; Beroukhim, R.; Norden, A. D.; Gerstner, E. R.; Betensky, R. A.; Batchelor, T. T. Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort study J. Neuro-Oncol. 2015, 121, 627– 634 DOI: 10.1007/s11060-014-1680-2[Crossref], [PubMed], [CAS], Google Scholar52bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFOku7fM&md5=45c84a46e3700560618c06bd4ba6a330Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort studyChheda, Milan G.; Wen, Patrick Y.; Hochberg, Fred H.; Chi, Andrew S.; Drappatz, Jan; Eichler, April F.; Yang, Daniel; Beroukhim, Rameen; Norden, Andrew D.; Gerstner, Elizabeth R.; Betensky, Rebecca A.; Batchelor, Tracy T.Journal of Neuro-Oncology (2015), 121 (3), 627-634CODEN: JNODD2; ISSN:0167-594X. (Springer)Targeting specific mol. alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to det. the max. tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, resp. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 mo (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule.(c) Kreisl, T. N.; McNeill, K. A.; Sul, J.; Iwamoto, F. M.; Shih, J.; Fine, H. A. A phase I/II trial of vandetanib for patients with recurrent malignant glioma Neuro-Oncology 2012, 14, 1519– 1526 DOI: 10.1093/neuonc/nos265(d) Subbiah, V.; Berry, J.; Roxas, M.; Guha-Thakurta, N.; Subbiah, I. M.; Ali, S. M.; McMahon, C.; Miller, V.; Cascone, T.; Pai, S.; Tang, Z.; Heymach, J. V. Systemic and CNS activity of the RET inhibitor vandetanib combined with the mTOR inhibitor everolimus in KIF5B-RET re-arranged non-small cell lung cancer with brain metastases Lung Cancer 2015, 89, 76– 79 DOI: 10.1016/j.lungcan.2015.04.004[Crossref], [PubMed], [CAS], Google Scholar52dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfkvVemsw%253D%253D&md5=3f397ffcdf953e5121326786659d730bSystemic and CNS activity of the RET inhibitor vandetanib combined with the mTOR inhibitor everolimus in KIF5B-RET re-arranged non-small cell lung cancer with brain metastasesSubbiah Vivek; Berry Jenny; Roxas Michael; Guha-Thakurta Nandita; Subbiah Ishwaria Mohan; Cascone Tina; Pai Shobha; Tang Zhenya; Heymach John V; Ali Siraj M; McMahon Caitlin; Miller VincentLung cancer (Amsterdam, Netherlands) (2015), 89 (1), 76-9 ISSN:.In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1-2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood-brain barrier penetration. A co-administration strategy to enhance the brain accumulation of vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood-brain barrier penetration. We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood-brain barrier penetration. A 74-year-old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5'RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood-brain barrier penetration by vandetanib in combination with everolimus. Further research is required in this setting.
- 53Reardon, D. A.; Pan, E.; Fan, J.; Mink, J.; Barboriak, D. P.; Vrendenburgh, J. J.; Desjardins, A.; Peters, K.; O’Brien, J. P.; Wen, P. Y. A phase 2 trial of the multitargeted kinase inhibitor lenvatinib (E7080) in patients with recurrent glioblastoma (GBM) and disease progression following prior bevacizumab treatment Ann. Oncol. 2012, 23 (Suppl. 9) 417PD
- 54Minocha, M.; Khurana, V.; Qin, B.; Pal, D.; Mitra, A. K. Co-administration strategy to enhance brain accumulation of vandetanib by modulating P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp1/Abcg2) mediated efflux with m-TOR inhibitors Int. J. Pharm. 2012, 434, 306– 314 DOI: 10.1016/j.ijpharm.2012.05.028[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVOis7zE&md5=ffd8765aeae0cdb94b7db0a7b775caebCo-administration strategy to enhance brain accumulation of vandetanib by modulating P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp1/Abcg2) mediated efflux with m-TOR inhibitorsMinocha, Mukul; Khurana, Varun; Qin, Bin; Pal, Dhananjay; Mitra, Ashim K.International Journal of Pharmaceutics (Amsterdam, Netherlands) (2012), 434 (1-2), 306-314CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)The objectives of this study were (i) to characterize the interaction of vandetanib with P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp1) in vitro and in vivo (ii) to study the modulation of P-gp and BCRP mediated efflux of vandetanib with specific transport inhibitors and m-TOR inhibitors, everolimus and temsirolimus. Cellular accumulation and bi-directional transport studies in MDCKII cell monolayers were conducted to delineate the role of efflux transporters on disposition of vandetanib. Brain distribution studies were conducted in male FVB wild-type mice with vandetanib administered i.v. either alone or in the presence of specific inhibitors and m-TOR inhibitors. In vitro studies suggested that vandetanib is a high affinity substrate of Bcrp1 but is not transported by P-gp. Interestingly, in vivo brain distribution studies in FVB wild type mice indicated that vandetanib penetration into the brain is restricted by both Bcrp1 and P-gp mediated active efflux at the blood brain barrier (BBB). Co-administration of elacridar, a dual P-gp/BCRP inhibitor increased the brain to plasma concn. ratio of vandetanib up to 5 fold. Of the two m-TOR pathway inhibitors examd., everolimus showed potent effect on modulating vandetanib brain penetration whereas no significant affect on vandetanib brain uptake was obsd. following temsirolimus co-administration. This finding could be clin. relevant as everolimus can provide synergistic pharmacol. effect in addn. to primary role of vandetanib efflux modulation at BBB for the treatment of brain tumors.
- 55Shumaker, R. C.; Aluri, J.; Fan, J.; Martinez, G.; Thompson, G. A.; Ren, M. Effect of fifampicin on the pharmacokinetics of lenvatinib in healthy adults Clin. Drug Invest. 2014, 34, 651– 659 DOI: 10.1007/s40261-014-0217-y[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFCqu7fN&md5=2d765646adf628f301c7c3a362683dc9Effect of Rifampicin on the Pharmacokinetics of Lenvatinib in Healthy AdultsShumaker, Robert C.; Aluri, Jagadeesh; Fan, Jean; Martinez, Gresel; Thompson, Gary A.; Ren, MinClinical Drug Investigation (2014), 34 (9), 651-659CODEN: CDINFR; ISSN:1173-2563. (Springer International Publishing AG)Background and Objectives: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor under clin. investigation in solid tumors. This study evaluated the influence of P-glycoprotein (P-gp) inhibition (single-dose rifampicin) and simultaneous cytochrome P 450 3A4 (CYP3A4)/P-gp induction (multiple-dose rifampicin) on lenvatinib pharmacokinetics. Methods: This Phase I, single-center, single-dose (lenvatinib mesylate 24 mg), open-label, sequential study enrolled 15 healthy volunteers. Three regimens were administered over three periods: Period (P) 1 (Days 1-8), P2 (Days 15-22) and P3 (Days 29-50), with a 14-day (first dose) and 28-day (second dose) washout period after lenvatinib mesylate administration (Day 1, Day 15 and Day 43). In P2, a single oral dose of rifampicin (600 mg) was coadministered with lenvatinib. In P3, rifampicin was administered daily (600 mg) for 21 days (Days 29-49). Serial blood samples were collected, and plasma concns. of total (protein bound + unbound) and free (unbound) lenvatinib and total metabolites (M1, M2, M3 and M5) were measured by validated high-performance liq. chromatog./tandem mass spectrometry. Results: Single-dose rifampicin (P-gp inhibition) increased area under the plasma concn.-time curve from time zero to infinity (AUC0-∞) of free and total lenvatinib by 32 and 31 %, resp. Multiple-dose rifampicin (simultaneous P-gp and CYP3A4 induction) decreased lenvatinib AUC0-∞ (total: 18 %; free: 9 %). Treatment-emergent adverse events were mild or moderate and occurred in 7 subjects (47 %). Conclusion: Lenvatinib exposure was increased by P-gp inhibition; however, based on free concns., simultaneous P-gp and CYP3A4 induction results met the prespecified bioequivalence 90 % confidence interval. Overall, the magnitude of these changes was relatively small, and likely not clin. meaningful.
- 56Banerjee, S.; Zvelebil, M.; Furet, P.; Mueller-Vieira, U.; Evans, D. B.; Dowsett, M.; Martin, L. A. The vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 inhibits aromatase Cancer Res. 2009, 69, 4716– 4723 DOI: 10.1158/0008-5472.CAN-08-4711
- 57(a) Gerstner, E. R.; Eichler, A. F.; Plotkin, S. R.; Drappatz; Doyle, C. L.; Xu, L.; Duda, D. G.; Wen, P. Y.; Jain, R. K.; Batchelor, T. T. Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide J. Neuro-Oncol. 2011, 103, 325– 332 DOI: 10.1007/s11060-010-0390-7[Crossref], [PubMed], [CAS], Google Scholar57ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmtl2nsLc%253D&md5=aa5ca98063908b011c83e27a952ef242Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomideGerstner, Elizabeth R.; Eichler, April F.; Plotkin, Scott R.; Drappatz, Jan; Doyle, Colin L.; Xu, Lei; Duda, Dan G.; Wen, Patrick Y.; Jain, Rakesh K.; Batchelor, Tracy T.Journal of Neuro-Oncology (2011), 103 (2), 325-332CODEN: JNODD2; ISSN:0167-594X. (Springer)Targeting angiogenesis in glioblastoma (GBM) may improve patient outcome by normalizing tumor vasculature and improving delivery of chemotherapeutics and oxygen. Consequently, concomitant administration of small mol. inhibitors of the VEGF pathway will likely have a pos. impact on chemoradiation treatment outcome. We conducted a Phase I study of vatalanib, a small mol. inhibitor of VEGFR, PDGFR, and c-kit in patients with newly diagnosed GBM receiving radiation, temozolomide, and an enzyme-inducing anti-epileptic drug in order to det. the MTD of vatalanib in this patient population. We incorporated circulating biomarker and SNP analyses and pharmacokinetic studies. Nineteen patients were enrolled and the MTD was not reached at the time of study termination. Vatalanib was well tolerated with only 2 DLTs (thrombocytopenia and elevated transaminases). Other grade 3/4 toxicities included leukopenia, lymphopenia, neutropenia, and hand-foot syndrome. There were no wound-healing complications. Of the 13 patients evaluable for a radiog. response, 2 had a partial response and 9 had stable disease. Vatalanib significantly increased PlGF and sVEGFR1 in plasma circulation and decreased sVEGFR2 and sTie2. Plasma collagen IV increased significantly by day 50 of treatment. Vatalanib was well tolerated and this study demonstrates the safety of oral small mol. inhibitors in newly diagnosed GBM patients. Blood biomarkers may be useful as pharmacodynamic markers of response to anti-angiogenic therapies.(b) Brandes, A. A.; Stupp, R.; Hau, P.; Lacombe, D.; Gorlia, T.; Tosoni, A.; Mirimanoff, R. O.; Kros, J. M.; van den Bent, M. J. EORTC study 26041-22041: phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma Eur. J. Cancer 2010, 46, 348– 354 DOI: 10.1016/j.ejca.2009.10.029(c) Reardon, D. A.; Egorin, M. J.; Desjardins, A.; Vredenburgh, J. J.; Beumer, J. H.; Lagattuta, T. F.; Gururangan, S.; Herndon, J. E.; Salvado, A. J.; Friedman, H. S. Phase I pharmacokinetic study of the VEGFR tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma Cancer 2009, 115, 2188– 2198 DOI: 10.1002/cncr.24213
- 58Yakes, F. M.; Chen, J.; Tan, J.; Yamaguchi, K.; Shi, Y.; Yu, P.; Qian, F.; Chu, F.; Bentzien, F.; Cancilla, B.; Orf, J.; You, A.; Laird, A. D.; Engst, S.; Lee, L.; Lesch, J.; Chou, Y. C.; Joly, A. H. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth Mol. Cancer Ther. 2011, 10, 2298– 2308 DOI: 10.1158/1535-7163.MCT-11-0264[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFylurnF&md5=3f573795ecee42deeee25005f991868fCabozantinib (XL184), a Novel MET and VEGFR2 Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and Tumor GrowthYakes, F. Michael; Chen, Jason; Tan, Jenny; Yamaguchi, Kyoko; Shi, Yongchang; Yu, Peiwen; Qian, Fawn; Chu, Felix; Bentzien, Frauke; Cancilla, Belinda; Orf, Jessica; You, Andrew; Laird, A. Douglas; Engst, Stefan; Lee, Lillian; Lesch, Justin; Chou, Yu-Chien; Joly, Alison H.Molecular Cancer Therapeutics (2011), 10 (12), 2298-2308CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a no. of human malignancies and has been assocd. with tumorigenesis. Cabozantinib (XL184) is a small-mol. kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a no. of other receptor tyrosine kinases that have also been implicated in tumor pathobiol., including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant redns. in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathol., resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an exptl. model of metastasis, which has been obsd. with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. Mol Cancer Ther; 10(12); 2298-308.
- 59Bhide, R. S.; Cai, Z. W.; Zhang, Y. Z.; Qian, L.; Wei, D.; Barbosa, S.; Lombardo, L. J.; Borzilleri, R. M.; Zheng, X.; Wu, L. I.; Barrish, J. C.; Kim, S. H.; Leavitt, K.; Mathur, A.; Leith, L.; Chao, S.; Wautlet, B.; Mortillo, S.; Jeyaseelan, R.; Kukral, D.; Hunt, J. T.; Kamath, A.; Fura, A.; Vyas, V.; Marathe, P.; D’Arienzo, C.; Derbin, G.; Fargnoli, J. Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor J. Med. Chem. 2006, 49, 2143– 2146 DOI: 10.1021/jm051106d
- 60Highlights of Prescribing Information. COMETRIQ. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf (accessed June 12, 2016) .
- 61Marathe, P. H.; Kamath, A. V.; Zhang, Y.; D’Arienzo, C.; Bhide, R.; Fargnoli, J. Preclinical pharmacokinetics and in vitro metabolism of brivanib (BMS-540215), a potent VEGFR2 inhibitor and its alanine ester prodrug brivanib alaninate Cancer Chemother. Pharmacol. 2009, 65, 55– 66 DOI: 10.1007/s00280-009-1002-0[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFegu77K&md5=d7ca6c43910437a12f64d70fe12c6e9cPreclinical pharmacokinetics and in vitro metabolism of brivanib (BMS-540215), a potent VEGFR2 inhibitor and its alanine ester prodrug brivanib alaninateMarathe, Punit H.; Kamath, Amrita V.; Zhang, Yueping; D'Arienzo, Celia; Bhide, Rajeev; Fargnoli, JosephCancer Chemotherapy and Pharmacology (2009), 65 (1), 55-66CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Brivanib alaninate is a prodrug of brivanib (BMS-540215), a potent oral VEGFR-2 inhibitor and is currently in development for the treatment of hepatocellular and colon carcinomas. In vitro and in vivo studies were conducted to characterize the preclin. pharmacokinetics and disposition of brivanib and brivanib alaninate, and antitumor efficacy in mice bearing human xenografts. In vitro studies were conducted in liver and intestinal fractions, plasma and Caco-2 cells to assess the metabolic stability. Pharmacokinetics of brivanib were detd. in preclin. species after administration of single i.v. or oral doses of both brivanib and brivanib alaninate. The antitumor efficacy was assessed at equimolar doses in nude mice bearing human tumor xenografts. Human efficacious dose was predicted based on projected human pharmacokinetic parameters and exposure at efficacious doses in the mouse efficacy models. In vitro and in vivo studies indicated that brivanib alaninate was efficiently converted to brivanib. Brivanib showed good brain penetration in rats consistent with its high intrinsic permeability and lack of active efflux in Caco-2 cells. The oral bioavailability of brivanib varied among species (22-88%) and showed dissoln. rate-limited absorption even when combined with org. co-solvents. Administration of brivanib as brivanib alaninate allowed completely aq. vehicles, and an improvement in the oral bioavailability (55-97%) was obsd. The clearance of brivanib in humans is anticipated to be low to intermediate (hepatic extn. ratio < 0.7), while its vol. of distribution is expected to be high. The min. efficacious dose of brivanib alaninate was detd. to be 60 mg/kg per day. Brivanib alaninate is rapidly and efficiently converted to the parent, brivanib, as demonstrated both in vitro and in vivo and offers an excellent mode to deliver brivanib orally.
- 62(a) De Groot, J. F.; Prados, M.; Urquhart, T.; Robertson, S.; Yaron, Y.; Sorensen, A. G.; Norton, A.; Batchelor, T.; Drappatz, J.; Wen, P. A phase II study of XL184 in patients (pts) with progressive glioblastoma multiforme (GBM) in first or second relapse J. Clin. Oncol. 2009, 27 (15s) 2047(b) Wen, P. Y.; Prados, M.; Schiff, D.; Reardon, D. A.; Cloughesy, T.; Mikkelsen, T.; Batchelor, T.; Drappatz, J.; Chamberlain, M. C.; De Groot, J. F. Phase II study of XL184 (BMS 907351), an inhibitor of MET, VEGFR2, and RET, in patients (pts) with progressive glioblastoma (GB) J. Clin. Oncol. 2010, 28, 2006
- 63Dowell, J.; Minna, J. D.; Kirkpatrick, P. Erlotinib hydrochloride Nat. Rev. Drug Discovery 2005, 4, 13– 14 DOI: 10.1038/nrd1612[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlsl2n&md5=acb463aa1a7ad35b770490a7c82800cdFresh from the Pipeline: Erlotinib hydrochlorideDowell, Jonathan; Minna, John D.; Kirkpatrick, PeterNature Reviews Drug Discovery (2005), 4 (1), 13-14CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)Erlotinib hydrochloride (Tarceva; OSI Pharmaceuticals/Genentech/Roche), a member of a class of targeted anticancer drugs that inhibit the activity of the epidermal growth factor receptor, was approved by the US FDA in Nov. 2004 for the treatment of advanced non-small-cell lung cancer after failure of at least one prior chemotherapy regimen. It is the first such drug to demonstrate an increase in survival in Phase III trials in patients with advanced non-small-cell lung cancer.
- 64Muhsin, M.; Graham, J.; Kirkpatrick, P. Gefitinib Nat. Rev. Drug Discovery 2003, 2, 515– 516 DOI: 10.1038/nrd1136[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXks1Oqsr0%253D&md5=e9fb650f4d801eb2026a795db1b9f6bdFresh from the pipeline: GefitinibMuhsin, Mohamed; Graham, Joanne; Kirkpatrick, PeterNature Reviews Drug Discovery (2003), 2 (7), 515-516CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)Gefitinib (Iressa; AstraZeneca) is the first in a new class of targeted anticancer drugs that inhibit the tyrosine kinase activity of the epidermal growth factor receptor. Following Japanese approval in 2002, gefitinib was approved by the US FDA in May 2003 for the treatment of advanced non-small-cell lung cancer after other treatment options have failed. Despite several setbacks during the development of gefitinib, might it now be back on the path to blockbuster status.
- 65Eskens, F. A. L. M.; Mom, C. H.; Planting, A. S. T.; Gieterma, J. A.; Amelsberg, A.; Huisman, H.; van Doorn, L.; Burger, H.; Stopfer, P.; Verweij, J.; de Vries, E. G. E. A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor I (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumors Br. J. Cancer 2008, 98, 80– 85 DOI: 10.1038/sj.bjc.6604108[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXisF2qtg%253D%253D&md5=96a0be31145bf1691640109d69ff5dc0A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumorsEskens, F. A. L. M.; Mom, C. H.; Planting, A. S. T.; Gietema, J. A.; Amelsberg, A.; Huisman, H.; van Doorn, L.; Burger, H.; Stopfer, P.; Verweij, J.; de Vries, E. G. E.British Journal of Cancer (2008), 98 (1), 80-85CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clin. activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhea despite treatment and grade 2 diarrhea lasting more than 7 days despite treatment). An addnl. 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics anal. in skin biopsies did not show significant changes in EGFR-assocd. biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was obsd. No partial or complete responses were obsd., stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD. British Journal of Cancer (2008) 98, 80-85. doi:10.1038/sj.bjc.6604108 www.bjcancer.com Published online 20 Nov. 2007.
- 66Finlay, M. R. V.; Anderton, M.; Ashton, S.; Ballard, P.; Bethel, P. A.; Box, M. R.; Bradbury, R. H.; Brown, S. J.; Butterworth, S.; Campbell, A.; Chorley, C.; Colclough, N.; Cross, D. A. E.; Currie, G. S.; Grist, M.; Hassall, L.; Hill, G. B.; James, D.; James, M.; Kemmitt, P.; Klinowska, T.; Lamont, G.; Lamont, S. G.; Martin, N.; McFarland, H. L.; Mellor, M. J.; Orme, J. P.; Perkins, D.; Perkins, P.; Richmond, G.; Smith, P.; Ward, R. A.; Waring, M. J.; Whittaker, D.; Wells, S.; Wrigley, G. L. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor J. Med. Chem. 2014, 57, 8249– 8267 DOI: 10.1021/jm500973a[ACS Full Text], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1KhurrI&md5=db9db624bb4324c2e22b1ab12035263bDiscovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the ReceptorFinlay, M. Raymond V.; Anderton, Mark; Ashton, Susan; Ballard, Peter; Bethel, Paul A.; Box, Matthew R.; Bradbury, Robert H.; Brown, Simon J.; Butterworth, Sam; Campbell, Andrew; Chorley, Christopher; Colclough, Nicola; Cross, Darren A. E.; Currie, Gordon S.; Grist, Matthew; Hassall, Lorraine; Hill, George B.; James, Daniel; James, Michael; Kemmitt, Paul; Klinowska, Teresa; Lamont, Gillian; Lamont, Scott G.; Martin, Nathaniel; McFarland, Heather L.; Mellor, Martine J.; Orme, Jonathon P.; Perkins, David; Perkins, Paula; Richmond, Graham; Smith, Peter; Ward, Richard A.; Waring, Michael J.; Whittaker, David; Wells, Stuart; Wrigley, Gail L.Journal of Medicinal Chemistry (2014), 57 (20), 8249-8267CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Epidermal growth factor receptor (EGFR) inhibitors have been used clin. in the treatment of nonsmall-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a no. of years. Despite encouraging clin. efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addn., EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. The authors describe herein the evolution of an early, mutant selective lead to the clin. candidate AZD9291 I, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclin. models, the clin. candidate was administered clin. to patients with T790M pos. EGFR-TKI resistant NSCLC and early efficacy has been obsd., accompanied by an encouraging safety profile.
- 67(a) Bartolotti, M.; Franceschi, E.; Brandes, A. A. EGF receptor tyrosine kinase inhibitors in the treatment of brain metastases from non-small-cell lung cancer Expert Rev. Anticancer Ther. 2012, 12, 1429– 1435 DOI: 10.1586/era.12.121[Crossref], [PubMed], [CAS], Google Scholar67ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVClu73N&md5=ab9824f9a0881ffae33f9765d8a43b97EGF receptor tyrosine kinase inhibitors in the treatment of brain metastases from non-small-cell lung cancerBartolotti, Marco; Franceschi, Enrico; Brandes, Alba ArielaExpert Review of Anticancer Therapy (2012), 12 (11), 1429-1435CODEN: ERATBJ; ISSN:1473-7140. (Expert Reviews Ltd.)A review. The incidence of brain metastasis (BM) is high in patients with non-small-cell lung cancer. Available std. therapeutic options, such as whole-brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. Novel agents, such as EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs), have now been included in std. non-small-cell lung cancer treatments. In a small subset of patients harboring EGFR-activating mutations, erlotinib and gefitinib administration was followed by a response rate of 70-80%, and a longer progression-free and overall survival than those obtained with std. chemotherapeutic regimens. However, since most of the larger studies on these agents have excluded BM patients from their series, few prospective data are available on the efficacy of these agents in this setting. In recent years, however, several authors have reported a growing no. of cases of partial and complete response in BM patients treated with EGFR TKIs. Data from retrospective series and Phase II studies also suggest that a response can be obtained using EGFR TKI treatment for patients with BM, esp. those harboring EGFR mutations.(b) Shimato, S.; Mitsudomi, T.; Kosaka, T.; Yatabe, Y.; Wakabayashi, T.; Mizuno, M.; Nakahara, N.; Hatano, H.; Natsume, A.; Ishii, D.; Yoshida, J. EGFR mutations in patients with brain metastases from lung cancer: association with the efficacy of gefitinib Neuro-Oncology 2006, 8, 137– 144 DOI: 10.1215/15228517-2005-002(c) Porta, R.; Sanchez-Torres, J. M.; Paz-Ares, L.; Massuti, B.; Reguart, N.; Mayo, C.; Lianes, P.; Queralt, C.; Guillem, V.; Salinas, P.; Catot, S.; Isla, D.; Pradas, A.; Gurpide, A.; de Castro, J.; Polo, E.; Puig, T.; Taron, M.; Colomer, R.; Rosell, R. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation Eur. Respir. J. 2011, 37, 624– 631 DOI: 10.1183/09031936.00195609[Crossref], [PubMed], [CAS], Google Scholar67chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmslemtLo%253D&md5=76106616b8b799d191c697b9295993baBrain metastases from lung cancer responding to erlotinib: the importance of EGFR mutationPorta, R.; Sanchez-Torres, J. M.; Paz-Ares, L.; Massuti, B.; Reguart, N.; Mayo, C.; Lianes, P.; Queralt, C.; Guillem, V.; Salinas, P.; Catot, S.; Isla, D.; Pradas, A.; Gurpide, A.; de Castro, J.; Polo, E.; Puig, T.; Taron, M.; Colomer, R.; Rosell, R.European Respiratory Journal (2011), 37 (3), 624-631CODEN: ERJOEI; ISSN:0903-1936. (European Respiratory Society)Median survival of patients with brain metastases from nonsmall cell lung cancer (NSCLC) is poor and more effective treatments are urgently needed. We have evaluated the efficacy of erlotinib in this setting and its assocn. with activating mutations in the epidermal growth factor receptor (EGFR) gene. We retrospectively identified patients with NSCLC and brain metastases treated with erlotinib. EGFR mutations in exons 19 and 21 were analyzed by direct sequencing. Efficacy and tolerability were compared according to EGFR mutational status. 69 NSCLC patients with brain metastases were identified, 17 of whom harbored EGFR mutations. Objective response rate in patients with EGFR mutations was 82.4%; no responses were obsd. in unselected patients (p<0.001). Median (95% CI) time to progression within the brain for patients harboring EGFR mutations was 11.7 (7.9-15.5) months, compared to 5.8 (5.2-6.4) months for control patients whose EGFR mutational status had not been assessed (p<0.05). Overall survival was 12.9 (6.2-19.7) months and 3.1 (2.5-3.9) months (p<0.001), resp. The toxicity of erlotinib was as expected and no differences between cohorts were obsd. Erlotinib is active in brain metastases from NSCLC; this clin. benefit is related to the presence of activating mutations in exons 19 or 21 of the EGFR gene.(d) Grommes, C.; Oxnard, G. R.; Kris, M. G.; Miller, V. A.; Pao, W.; Holodny, A. I.; Clarke, J. L.; Lassman, A. B. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer Neuro-Oncology 2011, 13, 1364– 1369 DOI: 10.1093/neuonc/nor121(e) Jackman, D. M.; Holmes, A. J.; Lindeman, N.; Wen, P. Y.; Kesari, S.; Borras, A. M.; Bailey, C.; de Jong, F.; Janne, P. A.; Johnson, B. E. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib J. Clin. Oncol. 2006, 24, 4517– 4520 DOI: 10.1200/JCO.2006.06.6126[Crossref], [PubMed], [CAS], Google Scholar67ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28rlslemtA%253D%253D&md5=391e78d72a39626276f7ffcbee76d1a1Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinibJackman David M; Holmes Alison J; Lindeman Neal; Wen Patrick Y; Kesari Santosh; Borras Ana M; Bailey Christopher; de Jong Francisca; Janne Pasi A; Johnson Bruce EJournal of clinical oncology : official journal of the American Society of Clinical Oncology (2006), 24 (27), 4517-20 ISSN:.There is no expanded citation for this reference.(f) Park, S. J.; Kim, H. T.; Lee, D. H.; Kim, K. P.; Kim, S.-W.; Suh, C.; Lee, J. S. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation Lung Cancer. 2012, 77, 556– 560 DOI: 10.1016/j.lungcan.2012.05.092
- 68Noronha, V.; Joshi, A.; Gokarn, A.; Sharma, V.; Patil, V.; Janu, A.; Purandare, N.; Chougule, A.; Jambhekar, N.; Prabhash, K. The importance of brain metastasis in EGFR mutation positive NSCLC patients Chemother. Res. Pract. 2014, 2014, 856156 DOI: 10.1155/2014/856156[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mvis1ykug%253D%253D&md5=fdb159a058dda4901c526fc0e9403138The Importance of Brain Metastasis in EGFR Mutation Positive NSCLC PatientsNoronha Vanita; Joshi Amit; Gokarn Anant; Sharma Vibhor; Chougule Anuradha; Prabhash Kumar; Patil Vijay; Janu Amit; Purandare Nilendu; Jambhekar NirmalaChemotherapy research and practice (2014), 2014 (), 856156 ISSN:2090-2107.Introduction. Brain metastasis is a poor prognostic marker in lung cancer. However it is not known whether amongst patients with EGFR mutation those with brain metastases have a worse outcome. Methods. We compared the survival outcomes between EGFR mutation positive patients with and without brain metastases. In this retrospective analysis of prospective database of all metastatic lung cancer patients at our centre between July 2009 and December 2012, patients were treated with either combination chemotherapy or oral TKI. All patients with brain metastases received whole brain radiation. Kaplan Meier method was used for survival analysis and compared using log rank test. Results. 101 patients with EGFR mutated, metastatic lung cancer were studied. Fourteen had brain metastases and 87 did not. The common EGFR mutations were exon 19 deletion (61.3%) and exon 21 L858R mutation (28.7%). Overall response was 64% in extracranial metastasis group as compared to 50% in brain metastasis group. There was a significant worsening of median OS in the patients with brain metastases (11.6 months) compared with only extracranial metastases (18.7 months), P = 0.029. Conclusion. Amongst patients with EGFR mutant NSCLC, the presence of brain metastases leads to a worse outcome as compared to patients with extracranial metastases alone.
- 69Weber, B.; Winterdahl, M.; Memon, A.; Sorensen, B. S.; Keiding, S.; Sorensen, L.; Nexo, E.; Meldgaard, P. Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor J. Thorac. Oncol. 2011, 6, 1287– 1289 DOI: 10.1097/JTO.0b013e318219ab87[Crossref], [PubMed], [CAS], Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MjmvV2rsA%253D%253D&md5=a00d4acc3aec6b71157da49fdf4732f0Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptorWeber Britta; Winterdahl Michael; Memon Ashfaque; Sorensen Boe S; Keiding Susanne; Sorensen Leif; Nexo Ebba; Meldgaard PeterJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (2011), 6 (7), 1287-9 ISSN:.INTRODUCTION: Drugs directed toward the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva®) and gefitinib (Iressa®), are used for the treatment of patients with advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. However, whether erlotinib actually enters into brain metastases has not been adequately elucidated. In this study, we investigated the accumulation of [11C]-erlotinib by positron emission tomography (PET) combined with computed tomography (CT) and magnetic resonance imaging (MRI). METHODS: A 32-year-old patient with NSCLC and multiple brain metastases was treated with first-line erlotinib. EGFR mutations were determined by analyzing a fine-needle lung tumor biopsy taken before the treatment. A PET/CT of the brain with [11C]-erlotinib was performed during treatment, and a MRI of the head and a CT of the chest were performed pre- and posttreatment. RESULTS: The primary lung tumor displayed an erlotinib-sensitizing exon 19 deletion in the EGFR gene, and [11C]-erlotinib PET/CT showed accumulation in the brain metastases. Posttreatment MRI and CT demonstrated regression of both brain metastases and primary lung tumor. CONCLUSION: Our data demonstrated that erlotinib accumulated in brain metastases in a NSCLC patient who responded to the treatment.
- 70Agarwal, S.; Manchanda, P.; Vogelbaum, M. A.; Ohlfest, J. R.; Elmquist, W. F. Function of the blood-brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma Drug Metab. Dispos. 2013, 41, 33– 39 DOI: 10.1124/dmd.112.048322
- 71Agarwal, S.; Sane, R.; Gallardo, J. L.; Ohlfest, J. R.; Elmquist, W. F. Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux J. Pharmacol. Exp. Ther. 2010, 334, 147– 155 DOI: 10.1124/jpet.110.167601[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXos1KltL8%253D&md5=ec97aadff2ab755740b1e6860126f71eDistribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active effluxAgarwal, Sagar; Sane, Ramola; Gallardo, Jose L.; Ohlfest, John R.; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2010), 334 (1), 147-155CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)Gefitinib is an orally active inhibitor of the epidermal growth factor receptor approved for use in patients with locally advanced or metastatic non-small cell lung cancer. It has also been evaluated in several clin. trials for treatment of brain tumors such as high-grade glioma. In this study, we investigated the influence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) on distribution of gefitinib to the central nervous system. In vitro studies conducted in Madin-Darby canine kidney II cells indicate that both P-gp and BCRP effectively transport gefitinib, limiting its intracellular accumulation. In vivo studies demonstrated that transport of gefitinib across the blood-brain barrier (BBB) is significantly limited. Steady-state brain-to-plasma (B/P) concn. ratios were 70-fold higher in the Mdr1a/b(-/-) Bcrp1(-/-) mice (ratio of approx. 7) compared with wild-type mice (ratio of approx. 0.1). The B/P ratio after oral administration increased significantly when gefitinib was coadministered with the dual P-gp and BCRP inhibitor elacridar. We investigated the integrity of tight junctions in the Mdr1a/b(-/-) Bcrp1(-/-) mice and found no difference in the brain inulin and sucrose space between the wild-type and Mdr1a/b(-/-) Bcrp1(-/-) mice. This suggested that the dramatic enhancement in the brain distribution of gefitinib is not due to a leakier BBB in these mice. These results show that brain distribution of gefitinib is restricted due to active efflux by P-gp and BCRP. This finding is of clin. significance for therapy in brain tumors such as glioma, where concurrent administration of a dual inhibitor such as elacridar can increase delivery and thus enhance efficacy of gefitinib.
- 72Peters, S.; Zimmerman, S.; Adjei, A. A. Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug-drug interactions Cancer Treat. Rev. 2014, 40, 917– 926 DOI: 10.1016/j.ctrv.2014.06.010[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFGmtbrP&md5=31253f81e203aa012a5d87ad29ff6fc3Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: Comparative pharmacokinetics and drug-drug interactionsPeters, Solange; Zimmermann, Stefan; Adjei, Alex A.Cancer Treatment Reviews (2014), 40 (8), 917-926CODEN: CTREDJ; ISSN:0305-7372. (Elsevier Ltd.)A review. The development of orally active small mol. inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients with activating mutations of the EGFR gene show sensitivity to, and clin. benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50-60% of cases being related to the appearance of a T790M gatekeeper mutation. Newer, irreversible EGFR-TKls - afatinib and dacomitinib - covalently bind to and inhibit multiple receptors in the ErbB family (EGFR, HER2 and HER4). These agents have been mainly evaluated for first-line treatment but also in the setting of acquired resistance to first-generation EGFR-TKls. Afatinib is the first ErbB family blocker approved for patients with NSCLC with activating EGFR mutations; dacomitinib is in late stage clin. development. Mutant-selective EGFR inhibitors (AZD9291, CO-1686, HM61713) that specifically target the T790M resistance mutation are in early development. The EGFR-TKIs differ in their spectrum of target kinases, reversibility of binding to EGFR receptor, pharmacokinetics and potential for drug-drug interactions, as discussed in this review. For the clinician, these differences are relevant in the setting of polymedicated patients with NSCLC, as well as from the perspective of innovative anticancer drug combination strategies.
- 73Highlights of Prescribing Information. TAGRISSO. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf Accessed June 12, 2016.
- 74Hoffknecht, P.; Tufman, A.; Wehler, T.; Pelzer, T.; Wiewrodt, R.; Schutz, M.; Serke, M.; Stohlmacher-Williams, J.; Marten, A.; Huber, R. M.; Dickgreber, N. J. Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease J. Thorac. Oncol. 2015, 10, 156– 163 DOI: 10.1097/JTO.0000000000000380[Crossref], [PubMed], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXisF2gsb4%253D&md5=90100bf9781e109f52c6498858c84ef3Efficacy of the Irreversible ErbB Family Blocker Afatinib in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI)-Pretreated Non-Small-Cell Lung Cancer Patients with Brain Metastases or Leptomeningeal DiseaseHoffknecht, Petra; Tufman, Amanda; Wehler, Thomas; Pelzer, Theo; Wiewrodt, Rainer; Schuetz, Martin; Serke, Monika; Stoehlmacher-Williams, Jan; Maerten, Angela; Huber, Rudolf Maria; Dickgreber, Nicolas J.Journal of Thoracic Oncology (2015), 10 (1), 156-163CODEN: JTOOB7; ISSN:1556-0864. (Lippincott Williams & Wilkins)Introduction: Afatinib is an effective first-line treatment in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) and has shown activity in patients progressing on EGFR-tyrosine kinase inhibitors (TKIs). First-line afatinib is also effective in patients with central nervous system (CNS) metastasis. Here we report on outcomes of pretreated NSCLC patients with CNS metastasis who received afatinib within a compassionate use program. Methods: Patients with NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment received afatinib. Medical history, patient demographics, EGFR mutational status, and adverse events including tumor progression were documented. Results: From 2010 to 2013, 573 patients were enrolled and 541 treated with afatinib. One hundred patients (66% female; median age, 60 years) had brain metastases and/or leptomeningeal disease with 74% having documented EGFR mutation. Median time to treatment failure for patients with CNS metastasis was 3.6 mo, and did not differ from a matched group of 100 patients without CNS metastasis. Thirty-five percent (11 of 31) of evaluable patients had a cerebral response, five (16%) responded exclusively in brain. Response duration (range) was 120 (21-395) days. Sixty-six percent (21 of 32) of patients had cerebral disease control on afatinib. Data from one patient with an impressive response showed an afatinib concn. in the cerebrospinal fluid of nearly 1 nMol. Conclusion: Afatinib appears to penetrate into the CNS with concns. high enough to have clin. effect on CNS metastases. Afatinib may therefore be an effective treatment for heavily pretreated patients with EGFR-mutated or EGFR-TKI-sensitive NSCLC and CNS metastasis.
- 75Hatanpaa, K. J.; Burma, S.; Zhao, D.; Habib, A. A. Epidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance Neoplasia 2010, 12, 675– 684 DOI: 10.1593/neo.10688
- 76(a) Mellinghoff, I. K.; Wang, M. Y.; Vivanco, I.; Haas-Kogan, D. A.; Zhu, S.; Dia, E. Q.; Lu, K. V.; Yoshimoto, K.; Huang, J. H. Y.; Chute, D. J.; Riggs, B. L.; Horvatch, S.; Liau, L. M.; Cavanee, W. K.; Rao, P. N.; Beroukhim, R.; Peck, T. C.; Lee, J. C.; Sellers, W. R.; Stokoe, D.; Prados, M.; Cloughesy, T. F.; Sawyers, C. L.; Mischel, P. S. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors N. Engl. J. Med. 2005, 353, 2012– 2024 DOI: 10.1056/NEJMoa051918[Crossref], [PubMed], [CAS], Google Scholar76ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1SrtrrE&md5=e19cb1d6924c5019a7ed5d5f1ccdb6d0Molecular determinants of the response of glioblastomas to EGFR kinase inhibitorsMellinghoff, Ingo K.; Wang, Maria Y.; Vivanco, Igor; Haas-Kogan, Daphne A.; Zhu, Shaojun; Dia, Ederlyn Q.; Lu, Kan V.; Yoshimoto, Koji; Huang, Julie H. Y.; Chute, Dennis J.; Riggs, Bridget L.; Horvath, Steve; Liau, Linda M.; Cavenee, Webster K.; Rao, P. Nagesh; Beroukhim, Rameen; Peck, Timothy C.; Lee, Jeffrey C.; Sellers, William R.; Stokoe, David; Prados, Michael; Cloughesy, Timothy F.; Sawyers, Charles L.; Mischel, Paul S.New England Journal of Medicine (2005), 353 (19), 2012-2024CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 % of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. We sequenced kinase domains in the EGFR and human EGFR type 2 (Her21neu) genes and analyzed the expression of EGFR, EGFR deletion mutantvariant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We detd. the mol. correlates of clin. response, validated them in an independent data set, and identified effects of the mol. abnormalities in vitro. Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 %. Pretreatment tissue was available for mol. anal. from 26 patients, 7 of whom had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly assocd. with a clin. response (P <0.001; odds ratio, 51; 95 % confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P = 0.001; odds ratio, 40; 95 % confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib. Coexpression of EGFRvIII and PTEN by glioblastoma cells is assocd. with responsiveness to EGFR kinase inhibitors.(b) Rich, J. N.; Reardon, D. A.; Peery, T.; Dowell, J. M.; Quinn, J. A.; Penne, K. L.; Wikstrand, C. J.; Van Duyn, L. B.; Dancey, J. E.; McLendon, R. E.; Kao, J. C.; Stenzel, T. T.; Rasheed, B. K. A.; Tourt-Uhlig, S. E.; Herndon, J. E.; Vredenburgh, J. J.; Sampson, J. H.; Friedman, A. H.; Bigner, D. D.; Friedman, H. S. Phase II trial of gefitinib in recurrent glioblastoma J. Clin. Oncol. 2004, 22, 133– 142 DOI: 10.1200/JCO.2004.08.110[Crossref], [PubMed], [CAS], Google Scholar76bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpsVKhsr8%253D&md5=4477591e92c2ce1272a21b1bbf8e451aPhase II trial of gefitinib in recurrent glioblastomaRich, Jeremy N.; Reardon, David A.; Peery, Terry; Dowell, Jeannette M.; Quinn, Jennifer A.; Penne, Kara L.; Wikstrand, Carol J.; van Duyn, Lauren B.; Dancey, Janet E.; McLendon, Roger E.; Kao, James C.; Stenzel, Timothy T.; Rasheed, B. K. Ahmed; Tourt-Uhlig, Sandra E.; Herndon, James E., II; Vredenburgh, James J.; Sampson, John H.; Friedman, Allan H.; Bigner, Darell D.; Friedman, Henry S.Journal of Clinical Oncology (2004), 22 (1), 133-142CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)The aim was to evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-wk cycles, and the 6-mo event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 wk, and the median overall survival (OS) time from treatment initiation was 39.4 wk. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea pos. predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.
- 77Walter, A. O.; Sjin, R. T.; Haringsma, H. J.; Ohashi, K.; Sun, J.; Lee, K.; Dubrovsky, A.; Labenski, M.; Zhu, Z.; Wang, Z.; Sheets, M.; St Martin, T.; Karp, R.; van Kalken, D.; Chaturvedi, P.; Niu, D.; Nacht, M.; Petter, R. C.; Westlin, W.; Lin, K.; Jaw-Tsai, S.; Raponi, M.; Van Dyke, T.; Etter, J.; Weaver, Z.; Pao, W.; Singh, J.; Simmons, A. D.; Harding, T. C.; Allen, A. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC Cancer Discovery 2013, 3, 1404– 1415 DOI: 10.1158/2159-8290.CD-13-0314[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvV2rtLvN&md5=3d111f4bf958f2fda6890fbc0e1d99f5Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLCWalter, Annette O.; Sjin, Robert Tjin Tham; Haringsma, Henry J.; Ohashi, Kadoaki; Sun, Jing; Lee, Kwangho; Dubrovskiy, Aleksandr; Labenski, Matthew; Zhu, Zhendong; Wang, Zhigang; Sheets, Michael; St. Martin, Thia; Karp, Russell; van Kalken, Dan; Chaturvedi, Prasoon; Niu, Deqiang; Nacht, Mariana; Petter, Russell C.; Westlin, William; Lin, Kevin; Jaw-Tsai, Sarah; Raponi, Mitch; Van Dyke, Terry; Etter, Jeff; Weaver, Zoe; Pao, William; Singh, Juswinder; Simmons, Andrew D.; Harding, Thomas C.; Allen, AndrewCancer Discovery (2013), 3 (12), 1404-1415CODEN: CDAIB2; ISSN:2159-8274. (American Association for Cancer Research)Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clin. efficacy is limited by acquired resistance, frequently driven by the EGFRT790M mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was obsd. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of addnl. mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC.
- 78(a) Yoshida, Y.; Ozawa, T.; Butowski, N.; Shen, W.; Brown, D.; Pederson, H.; James, D. Preclinical evaluation of NT-113, a novel ERBB inhibitor optimized for CNS biodistribution Neuro-Oncology 2013, 15 (Suppl.) ET-00(b) Yoshida, Y.; Ozawa, T.; Yao, T.-W.; Shen, W.; Brown, D.; Parsa, A. T.; Raizer, J. J.; Cheng, S.-Y.; Stegh, A. H.; Mazar, A. P.; Giles, F. J.; Sarkaria, J. N.; Butowski, N.; Nicolaides, T.; James, C. D. NT113, a pan-ERBB inhibitor with high brain penetrance, inhibits the growth of glioblastoma xenografts with EGFR amplification Mol. Cancer Ther. 2014, 13, 2919– 2929 DOI: 10.1158/1535-7163.MCT-14-0306[Crossref], [PubMed], [CAS], Google Scholar78bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVCju7jM&md5=b500ebf948e4eee2d604ed99d87382b9NT113, a Pan-ERBB Inhibitor with High Brain Penetrance, Inhibits the Growth of Glioblastoma Xenografts with EGFR AmplificationYoshida, Yasuyuki; Ozawa, Tomoko; Yao, Tsun-Wen; Shen, Wang; Brown, Dennis; Parsa, Andrew T.; Raizer, Jeffrey J.; Cheng, Shi-Yuan; Stegh, Alexander H.; Mazar, Andrew P.; Giles, Francis J.; Sarkaria, Jann N.; Butowski, Nicholas; Nicolaides, Theodore; James, C. DavidMolecular Cancer Therapeutics (2014), 13 (12), 2919-2929CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)This report describes results from our anal. of the activity and biodistribution of a novel pan-ERBB inhibitor, NT113, when used in treating mice with intracranial glioblastoma (GBM) xenografts. Approaches used in this investigation include: bioluminescence imaging (BLI) for monitoring intracranial tumor growth and response to therapy; detn. of survival benefit from treatment; anal. of tumor IHC reactivity for indication of treatment effect on proliferation and apoptotic response; Western blot anal. for detn. of effects of treatment on ERBB and ERBB signaling mediator activation; and high-performance liq. chromatog. for detn. of NT113 concn. in tissue exts. from animals receiving oral administration of inhibitor. Our results show that NT113 is active against GBM xenografts in which wild-type EGFR or EGFRvIII is highly expressed. In expts. including lapatinib and/or erlotinib, NT113 treatment was assocd. with the most substantial improvement in survival, as well as the most substantial tumor growth inhibition, as indicated by BLI and IHC results. Western blot anal. results indicated that NT113 has inhibitory activity, both in vivo and in vitro, on ERBB family member phosphorylation, as well as on the phosphorylation of downstream signaling mediator Akt. Results from the anal. of animal tissues revealed significantly higher NT113 normal brain-to-plasma and intracranial tumor-to-plasma ratios for NT113, relative to erlotinib, indicating superior NT113 partitioning to intracranial tissue compartments. These data provide a strong rationale for the clin. investigation of NT113, a novel ERBB inhibitor, in treating patients with GBM.
- 79Zeng, Q.; Wang, J.; Cheng, Z.; Chen, K.; Johnstrom, P.; Varnas, K.; Li, D. Y.; Yang, Z. F.; Zhang, X. Discovery and evaluation of clinical candidate AZD3759, a potent, oral active, central nervous system-penetrant, epidermal growth factor receptor tyrosine kinase inhibitor J. Med. Chem. 2015, 58, 8200– 8215 DOI: 10.1021/acs.jmedchem.5b01073[ACS Full Text], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtl2qu7rI&md5=1bfaf33c6fa94a490707b3673314eeb5Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase InhibitorZeng, Qingbei; Wang, Jiabing; Cheng, Ziqiang; Chen, Kan; Johnstrom, Peter; Varnas, Katarina; Li, David Yunzhi; Yang, Zhen Fan; Zhang, XiaolinJournal of Medicinal Chemistry (2015), 58 (20), 8200-8215CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recent reports suggest that an increasing no. of patients with lung cancer, esp. those with activating mutations of the epidermal growth factor receptor (EGFR), also present with brain metastases and leptomeningeal metastases. These patients have poor prognosis as there are no approved drugs for these indications. Available agents have poor efficacy for these patients even at well above their std. dose. Herein, the authors report the discovery I (AZD3759), an investigational drug currently in Phase 1 clin. trial, which has excellent central nervous system penetration and which induces profound regression of brain metastases in a mouse model.
- 80Ströbele, S.; Schneider, M.; Schneele, L.; Siegelin, M. D.; Nonnenmacher, L.; Zhou, S.; Karpel-Massle, G.; Westhoff, M.-A.; Halatsch, M.-E.; Debatin, K.-M. A potential role for the inhibition of PI3K signaling in glioblastoma therapy PLoS One 2015, 10, e0131670 DOI: 10.1371/journal.pone.0131670
- 81Akhavan, D.; Cloughesy, T. F.; Mischel, P. S. mTOR signaling in glioblastoma: lessons learned from bench to bedside Neuro-Oncology 2010, 12, 882– 889 DOI: 10.1093/neuonc/noq052
- 82The Cancer Genome Atlas Network Comprehensive genomic characterization defines human glioblastoma genes and core pathways Nature 2008, 455, 1061– 1068 DOI: 10.1038/nature07385
- 83Westhoff, M.-A.; Karpel-Massler, G.; Brühl, O.; Enzenmüller, S.; La Ferla-Brühl, K.; Siegelin, M. D.; Nonnenmacher, L.; Debatin, K.-M. A critical evaluation of PI3K inhibition in glioblastoma and neruoblastoma therapy Mol. Cell. Ther. 2014, 2, 32 DOI: 10.1186/2052-8426-2-32[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MbhvFSmuw%253D%253D&md5=f9454544b227292f5bb6a069cda03542A critical evaluation of PI3K inhibition in Glioblastoma and Neuroblastoma therapyWesthoff Mike-Andrew; Enzenmuller Stefanie; Nonnenmacher Lisa; Debatin Klaus-Michael; Karpel-Massler Georg; Bruhl Oliver; La Ferla-Bruhl Katia; Siegelin Markus DMolecular and cellular therapies (2014), 2 (), 32 ISSN:.Members of the PI3K/Akt/mTor signaling cascade are among the most frequently altered proteins in cancer, yet the therapeutic application of pharmacological inhibitors of this signaling network, either as monotherapy or in combination therapy (CT) has so far not been particularly successful. In this review we will focus on the role of PI3K/Akt/mTOR in two distinct tumors, Glioblastoma multiforme (GBM), an adult brain tumor which frequently exhibits PTEN inactivation, and Neuroblastoma (NB), a childhood malignancy that affects the central nervous system and does not harbor any classic alterations in PI3K/Akt signaling. We will argue that inhibitors of PI3K/Akt signaling can be components for potentially promising new CTs in both tumor entities, but further understanding of the signal cascade's complexity is essential for successful implementation of these CTs. Importantly, failure to do this might lead to severe adverse effects, such as treatment failure and enhanced therapy resistance.
- 84Mohd Sharial, M. S. N.; Crown, J.; Hennessy, B. T. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer Ann. Oncol. 2012, 23, 3007– 3016 DOI: 10.1093/annonc/mds200[Crossref], [PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38flslWitg%253D%253D&md5=4093d2b285b188ffe24c42d942d529d0Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancerMohd Sharial M S N; Crown J; Hennessy B TAnnals of oncology : official journal of the European Society for Medical Oncology / ESMO (2012), 23 (12), 3007-16 ISSN:.BACKGROUND: Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed. DESIGN: A literature search was performed to identify proposed mechanisms of resistance to HER2-targeted therapy and identified novel targets in clinical development for treating HER2-resistant disease. RESULTS: Proposed HER2-resistance mechanisms include impediments to HER2-inhibitor binding, signaling through alternative pathways, upregulation of signaling pathways downstream of HER2, and failure to elicit an appropriate immune response. Although continuing HER2 inhibition beyond progression may provide an additional clinical benefit, the availability of novel therapies targeting different mechanisms of action could improve outcomes. The developmental strategy with the most available data is targeting the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) pathway. The oral mTOR inhibitor everolimus has shown promising activity in combination with chemotherapy and trastuzumab in trastuzumab-refractory, advanced breast cancer. CONCLUSIONS: Non-HER2-targeted therapy is a promising means of overcoming resistance to HER2-targeted treatment. Ongoing clinical studies will provide additional information on the efficacy and safety of novel targeted therapies in HER2-resistant advanced breast cancer.
- 85Wen, P. Y.; Lee, E. Q.; Reardon, D. A.; Ligon, K. L.; Yung, W. K. A. Current clinical development of PI3K pathway inhibitors in glioblastoma Neuro-Oncology 2012, 14, 819– 829 DOI: 10.1093/neuonc/nos117
- 86Heffron, T. P.; Ndubaku, C. O.; Salphati, L.; Alicke, B.; Cheong, J.; Drobnick, J.; Edgar, K.; Gould, S. E.; Lee, L. B.; Lesnick, J. D.; Lewis, C.; Nonomiya, J.; Pang, J.; Plise, E. G.; Sideris, S.; Wallin, J.; Wang, L.; Zhang, X.; Olivero, A. G. Discovery of clinical development candidate GDC-0084, a brain penetrant inhibitor of PI3K and mTOR ACS Med. Chem. Lett. 2016, 7, 351– 356 DOI: 10.1021/acsmedchemlett.6b00005
- 87Burger, M. T.; Pecchi, S.; Wagman, A.; Ni, Z.-J.; Knapp, M.; Hendrickson, T.; Atallah, G.; Pfister, K.; Zhang, Y.; Bartulis, S.; Frazier, K.; Ng, S.; Smith, A.; Verhagen, J.; Haznedar, J.; Huh, K.; Iwanowicz, E.; Xin, X.; Menezes, D.; Merritt, H.; Lee, I.; Wiesmann, M.; Kaufman, S.; Crawford, K.; Chin, M.; Bussiere, D.; Shoemaker, K.; Zaror, I.; Maira, S.-M.; Voliva, C. F. Identification of NVP-BKM120 as a potent, selective, orally bioavailable Class I PI3 kinase inhibitor for treating cancer ACS Med. Chem. Lett. 2011, 2, 774– 779 DOI: 10.1021/ml200156t[ACS Full Text], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVOktrrI&md5=5d00d73dda1fc0d8f0f07d12900282edIdentification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating CancerBurger, Matthew T.; Pecchi, Sabina; Wagman, Allan; Ni, Zhi-Jie; Knapp, Mark; Hendrickson, Thomas; Atallah, Gordana; Pfister, Keith; Zhang, Yanchen; Bartulis, Sarah; Frazier, Kelly; Ng, Simon; Smith, Aaron; Verhagen, Joelle; Haznedar, Joshua; Huh, Kay; Iwanowicz, Ed; Xin, Xiaohua; Menezes, Daniel; Merritt, Hanne; Lee, Isabelle; Wiesmann, Marion; Kaufman, Susan; Crawford, Kenneth; Chin, Michael; Bussiere, Dirksen; Shoemaker, Kevin; Zaror, Isabel; Maira, Sauveur-Michel; Voliva, Charles F.ACS Medicinal Chemistry Letters (2011), 2 (10), 774-779CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Phosphoinositide-3-kinases (PI3Ks) are important oncol. targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clin. trials for the treatment of cancer.
- 88Ihle, N. T.; Williams, R.; Chow, S.; Chew, W.; Berggren, M. I.; Paine-Murrieta, G.; Minion, D. J.; Halter, R. J.; Wipf, P.; Abraham, R.; Kirkpatrick, L.; Powis, G. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling Mol. Cancer Ther. 2004, 3, 763– 772[PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXls1anu7k%253D&md5=8c311288f085007b0f1b4846ea4aec37Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signalingIhle, Nathan T.; Williams, Ryan; Chow, Sherry; Chew, Wade; Berggren, Margareta I.; Paine-Murrieta, Gillian; Minion, Daniel J.; Halter, Robert J.; Wipf, Peter; Abraham, Robert; Kirkpatrick, Lynn; Powis, GarthMolecular Cancer Therapeutics (2004), 3 (7), 763-772CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)We have developed biol. stable semisynthetic viridins as inhibitors of phosphoinositide (PtdIns)-3-kinases. The most active compd. was PX-866, which inhibited purified PtdIns-3-kinase with an IC50 of 0.1 nmol/L and PtdIns-3-kinase signaling measured by phospho-Ser473-Akt levels in HT-29 colon cancer cells with an IC50 of 20 nmol/L. PX-866 administered to mice at 10 mg/kg inhibited phospho-Ser473-Akt in HT-29 colon tumor xenografts up to 80% with recovery taking >48 h after p.o. administration but more rapidly after i.v. or i.p. administration. PX-866 was eliminated from mouse plasma with a half-life of 18 min and a clearance of 360 mL/min/kg following i.v. administration and, when administered i.p. or p.o., showed first-pass metab. with sequential N-deallylation. Synthetic stds. of the N-deallylated metabolites of PX-866 inhibited PtdIns-3-kinase at low nanomolar per L concns. PX-866 exhibited in vivo antitumor activity against s.c. OvCar-3 human ovarian cancer and A-549 human lung cancer xenografts in immunodefficient mice with log cell kills up to 1.2. PX-866 also increased the antitumor activity of cisplatin against A-549 xenografts and radiation treatment against OvCar-3 xenografts. The results show that PX-866 is a biol. stable broad-spectrum PtdIns-3-kinase inhibitor with good pharmacokinetics that causes prolonged inhibition of PtdIns-3-kinase signaling in human tumor xenografts. PX-866 exhibits single agent in vivo antitumor activity and increases the antitumor effects of cisplatin and radiation treatment.
- 89Foster, P.; Yamaguchi, K.; Hsu, P. P.; Qian, F.; Du, X.; Wu, J.; Won, K. A.; Yu, P.; Jaeger, C. T.; Zhang, W.; Marlowe, C. K.; Keast, P.; Abulafia, W.; Chen, J.; Young, J.; Plonowski, A.; Yakes, F. M.; Chu, F.; Engell, K.; Bentzien, F.; Lam, S. T.; Dale, S.; Yturralde, O.; Matthews, D. J.; Lamb, P.; Laird, A. D. The selective PI3K inhibitor XL147 (SAR245408) inhibits tumor growth and survival and potentiates the activity of chemotherapeutic agents in preclinical models Mol. Cancer Ther. 2015, 14, 931– 940 DOI: 10.1158/1535-7163.MCT-14-0833[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmtlCit7o%253D&md5=3f20e5ab563c242807ddb021616d994eThe Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor ModelsFoster, Paul; Yamaguchi, Kyoko; Hsu, Pin P.; Qian, Fawn; Du, Xiangnan; Wu, Jianming; Won, Kwang-Ai; Yu, Peiwen; Jaeger, Christopher T.; Zhang, Wentao; Marlowe, Charles K.; Keast, Paul; Abulafia, Wendy; Chen, Jason; Young, Jenny; Plonowski, Artur; Yakes, F. Michael; Chu, Felix; Engell, Kelly; Bentzien, Frauke; Lam, Sanh T.; Dale, Stephanie; Yturralde, Olivia; Matthews, David J.; Lamb, Peter; Laird, A. DouglasMolecular Cancer Therapeutics (2015), 14 (4), 931-940CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently obsd. in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 h. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that obsd. with the corresponding single agents. Mol Cancer Ther; 14(4); 931-40. ©2015 AACR.
- 90Yu, P.; Laird, A. D.; Du, X.; Wu, J.; Won, K.; Yamaguchi, K.; Hsu, P. P.; Qian, F.; Jaeger, C. T.; Zhang, W.; Buhr, C. A.; Shen, P.; Abulafia, W.; Chen, J.; Young, J.; Plonowski, A.; Yakes, F. M.; Chu, F.; Lee, M.; Bentzien, F.; Lam, S. T.; Dale, S.; Matthews, D. J.; Lamb, P.; Foster, P. Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathway Mol. Cancer Ther. 2014, 13, 1078– 1091 DOI: 10.1158/1535-7163.MCT-13-0709[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnsFWjsLw%253D&md5=d300f7d62af36c9c9eeb6a5826e48eb2Characterization of the Activity of the PI3K/mTOR Inhibitor XL765 (SAR245409) in Tumor Models with Diverse Genetic Alterations Affecting the PI3K PathwayYu, Peiwen; Laird, A. Douglas; Du, Xiangnan; Wu, Jianming; Won, Kwang-Ai; Yamaguchi, Kyoko; Hsu, Pin Pin; Qian, Fawn; Jaeger, Christopher T.; Zhang, Wentao; Buhr, Chris A.; Shen, Paula; Abulafia, Wendy; Chen, Jason; Young, Jenny; Plonowski, Arthur; Yakes, F. Michael; Chu, Felix; Lee, Michelle; Bentzien, Frauke; Lam, Sanh Tan; Dale, Stephanie; Matthews, David J.; Lamb, Peter; Foster, PaulMolecular Cancer Therapeutics (2014), 13 (5), 1078-1091CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Activation of the PI3K (phosphoinositide 3-kinase) pathway is a frequent occurrence in human tumors and is thought to promote growth, survival, and resistance to diverse therapies. Here, we report pharmacol. characterization of the pyridopyrimidinone deriv. XL765 (SAR245409), a potent and highly selective pan inhibitor of class I PI3Ks (α, β, γ, and δ) with activity against mTOR. Broad kinase selectivity profiling of >130 protein kinases revealed that XL765 is highly selective for class I PI3Ks and mTOR over other kinases. In cellular assays, XL765 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL765 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approx. 24 h. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is assocd. with antiproliferative, antiangiogenic, and proapoptotic effects. Mol Cancer Ther; 13(5); 1078-91. ©2014 AACR.
- 91Lin, N. U. Targeted therapies in brain metastases Curr. Treat. Options Neurol. 2014, 16, 276 DOI: 10.1007/s11940-013-0276-z[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c3oslOrtQ%253D%253D&md5=ca3b1092fd955c72d4e54a9910dd65fbTargeted therapies in brain metastasesLin Nancy UCurrent treatment options in neurology (2014), 16 (1), 276 ISSN:1092-8480.OPINION STATEMENT: Brain metastases are a major clinical problem in patients with advanced breast cancer, lung cancer, melanoma, and renal cell carcinoma. Initial treatment for patients with brain metastases typically includes radiotherapy, either whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or both. Surgical resection is generally reserved for good prognosis patients with limited/controlled extracranial metastases and a single brain lesion. Once patients progress through upfront treatment, the treatment approach is quite variable and there is no clearly defined standard-of-care. Over the past decade, the role of systemic therapies and in particular, targeted therapies has been increasingly explored in patients with brain metastases from solid tumors. For example, lapatinib has been studied as monotherapy, and in combination with capecitabine, in patients with HER2-positive breast cancer, and activity has been observed in both the upfront and refractory settings. In patients with nonsmall cell lung cancer (NSCLC), central nervous system (CNS) activity has been reported with gefinitib and erlotinib. Finally, in melanoma, the B-raf inhibitors vemurafenib and dabrafenib, and the immunomodulator, ipilumimab, have reported CNS activity. Moving forward, the challenge will be to understand how to optimize the activity of targeted agents in the CNS and how to best incorporate them into the current treatment paradigms in order to improve outcomes for this patient population.
- 92Sutherlin, D. P.; Sampath, D.; Berry, M.; Castanedo, G.; Chang, Z.; Chuckowree, I.; Dotson, J.; Folkes, A.; Friedman, L.; Goldsmith, R.; Heffron, T.; Lee, L.; Lesnick, J.; Lewis, C.; Mathieu, S.; Nonomiya, J.; Olivero, A.; Pang, J.; Prior, W. W.; Salphati, L.; Sideris, S.; Tian, Q.; Tsui, V.; Wan, N. C.; Wang, S.; Wiesmann, C.; Wong, S.; Zhu, B.-Y. Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer J. Med. Chem. 2010, 53, 1086– 1097 DOI: 10.1021/jm901284w
- 93Folkes, A. J.; Ahmadi, K.; Alderton, W. K.; Alix, S.; Baker, S. J.; Box, G.; Chuckowree, I. S.; Clarke, P. A.; Depledge, P.; Eccles, S. A.; Friedman, L. S.; Hayes, A.; Hancox, T. C.; Kugendradas, A.; Lensun, L.; Moore, P.; Olivero, A. G.; Pang, J.; Patel, S.; Pergl-Wilson, G. H.; Raynaud, F. I.; Robson, A.; Saghir, N.; Salphati, L.; Sohal, S.; Ultsch, M. H.; Valenti, M.; Wallweber, H. J.; Wan, N. C.; Wiesmann, C.; Workman, P.; Zhyvoloup, A.; Zvelebil, M. J.; Shuttleworth, S. J. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer J. Med. Chem. 2008, 51, 5522– 5532 DOI: 10.1021/jm800295d[ACS Full Text], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVCmsr7E&md5=742084954685353ceaf18660ab3a0703The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancerFolkes, Adrian J.; Ahmadi, Khatereh; Alderton, Wendy K.; Alix, Sonia; Baker, Stewart J.; Box, Gary; Chuckowree, Irina S.; Clarke, Paul A.; Depledge, Paul; Eccles, Suzanne A.; Friedman, Lori S.; Hayes, Angela; Hancox, Timothy C.; Kugendradas, Arumugam; Lensun, Letitia; Moore, Pauline; Olivero, Alan G.; Pang, Jodie; Patel, Sonal; Pergl-Wilson, Giles H.; Raynaud, Florence I.; Robson, Anthony; Saghir, Nahid; Salphati, Laurent; Sohal, Sukhjit; Ultsch, Mark H.; Valenti, Melanie; Wallweber, Heidi J. A.; Wan, Nan Chi; Wiesmann, Christian; Workman, Paul; Zhyvoloup, Alexander; Zvelebil, Marketa J.; Shuttleworth, Stephen J.Journal of Medicinal Chemistry (2008), 51 (18), 5522-5532CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivs. were prepd. and evaluated as inhibitors of PI3 kinase p110α. The synthesis, biol. activity, and further profiling of these compds. are described. This work resulted in the discovery of GDC-0941 (I) which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clin. trials for the treatment of cancer.
- 94(a) Heffron, T. P.; Salphati, L.; Alicke, B.; Cheong, J.; Dotson, J.; Edgar, K.; Goldsmith, R.; Gould, S. E.; Lee, L. B.; Lesnick, J. D.; Lewis, C.; Ndubaku, C. O.; Nonomiya, J.; Olivero, A. G.; Pang, J.; Plise, E. G.; Sideris, S.; Trapp, S.; Wallin, J.; Wang, L.; Zhang, X. The design and identification of brain penetrant inhibitors of phosphoinositide 3-kinase a J. Med. Chem. 2012, 55, 8007– 8020 DOI: 10.1021/jm300867c(b) Salphati, L.; Heffron, T. P.; Alicke, B.; Nishimura, M.; Barck, K.; Carano, R. A.; Cheong, J.; Edgar, K.; Greve, J.; Kharbanda, S.; Koeppen, H.; Lau, S.; Lee, L. B.; Pang, J.; Plise, E. G.; Pokorny, J. L.; Reslan, H. B.; Sarkaria, J. N.; Wallin, J. J.; Zhang, X.; Gould, S. E.; Olivero, A. G.; Phillips, H. S. Targeting the PI3K pathway in the brain – efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier Clin. Cancer Res. 2012, 18, 6239– 6248 DOI: 10.1158/1078-0432.CCR-12-0720[Crossref], [PubMed], [CAS], Google Scholar94bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs12jur3J&md5=04450de4d9e3106d7f4d8fb831f9e9acTargeting the PI3K Pathway in the Brain-Efficacy of a PI3K Inhibitor Optimized to Cross the Blood-Brain BarrierSalphati, Laurent; Heffron, Timothy P.; Alicke, Bruno; Nishimura, Merry; Barck, Kai; Carano, Richard A.; Cheong, Jonathan; Edgar, Kyle A.; Greve, Joan; Kharbanda, Samir; Koeppen, Hartmut; Lau, Shari; Lee, Leslie B.; Pang, Jodie; Plise, Emile G.; Pokorny, Jenny L.; Reslan, Hani Bou; Sarkaria, Jann N.; Wallin, Jeffrey J.; Zhang, Xiaolin; Gould, Stephen E.; Olivero, Alan G.; Phillips, Heidi S.Clinical Cancer Research (2012), 18 (22), 6239-6248CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: Glioblastoma (GBM), the most common primary brain tumor in adults, presents a high frequency of alteration in the PI3K pathway. Our objectives were to identify a dual PI3K/mTOR inhibitor optimized to cross the blood-brain barrier (BBB) and characterize its brain penetration, pathway modulation in the brain and efficacy in orthotopic xenograft models of GBM. Exptl. Design: Physicochem. properties of PI3K inhibitors were optimized using in silico tools, leading to the identification of GNE-317. This compd. was tested in cells overexpressing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Following administration to mice, GNE-317 plasma and brain concns. were detd., and phosphorylated biomarkers (pAkt, p4EBP1, and pS6) were measured to assess PI3K pathway suppression in the brain. GNE-317 efficacy was evaluated in the U87, GS2, and GBM10 orthotopic models of GBM. Results: GNE-317 was identified as having physicochem. properties predictive of low efflux by P-gp and BCRP. Studies in transfected MDCK cells showed that GNE-317 was not a substrate of either transporter. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-h postdose. GNE-317 was efficacious in the U87, GS2, and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, resp. Conclusions: These results indicated that specific optimization of PI3K inhibitors to cross the BBB led to potent suppression of the PI3K pathway in healthy brain. The efficacy of GNE-317 in 3 intracranial models of GBM suggested that this compd. could be effective in the treatment of GBM. Clin Cancer Res; 18(22); 6239-48. ©2012 AACR.
- 95Maira, M.; Schnell, C.; Lollini, P.; Chouaid, C.; Schmid, P.; Nanni, P.; Lam, D.; Di Tomaso, E.; C. Massacesi, C.; Rodon, J. Preclinical and preliminary clinical activity of NVP-BKM-120, an oral pan-class I PI3K inhibitor, in the brain Ann. Oncol. 2012, 23 (Suppl.) 1675
- 96Wen, P. Y.; Yung, W. K. A.; Mellinghoff, I. K.; Ramkissoon, S.; Alexander, B. M.; Rinne, M. L.; Colman, H.; Omuro, A. M. P.; DeAngelis, L. M.; Gilbert, M. R.; De Groot, J. F.; Cloughesy, T. F.; Chi, A. S.; Lee, E. Q.; Nayak, L.; Betchelor, T.; Chang, S. M.; Prados, M.; Reardon, D. A.; Ligon, K. Phase II trial of the phosphatidylinositol-3 kinase (PI3K) inhibitor buparlisib (BKM120) in recurrent glioblastoma J. Clin. Oncol. 2014, 32 (Suppl.) 2019
- 97Cmiljanovic, V.; Cmiljanovic, N.; Marone, R.; Beaufils, F.; Zhang, X.; Zvelebil, M.; Hebeisen, P.; Lang, M.; Mestan, J.; Melone, A.; Bohnacker, T.; Gaudio, E.; Tarantelli, C.; Bertoni, F.; Ritschard, R.; Pretre, V.; Wicki, A.; Fabbro, D.; Hillmann, P.; Williams, R.; Giese, B.; Wymann, M. P. Abstract 2664: PQR309: structure-based design, synthesis and biological evaluation of a novel, selective, dual pan-PI3K/mTOR inhibitor Cancer Res. 2015, 75 (Suppl.) 2664 DOI: 10.1158/1538-7445.AM2015-2664
- 98Cmiljanovic, V.; Ettlin, R. A.; Beaufils, F.; Dieterle, W.; Hillmann, P.; Mestan, J.; Melone, A.; Bohnacker, T.; Lang, M.; Cmiljanovic, N.; Giese, B.; Hebeisen, P.; Wymann, M. P.; Fabbro, D. Abstract 4514: PQR309: A potent, brain-penetrant, dual pan-PI3K/mTOR inhibitor with excellent oral bioavailability and tolerability Cancer Res. 2015, 75 (Suppl.) 4514 DOI: 10.1158/1538-7445.AM2015-4514
- 99Lannutti, B. J.; Meadows, S. A.; Herman, S. E. M.; Kashishian, A.; Steiner, B.; Johnson, A. J.; Byrd, J. C.; Tyner, J. W.; Loriaux, M. M.; Deininger, M.; Druker, B. J.; Puri, K. D.; Ulrich, R. G.; Giese, N. A. CAL-101, a p100d selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability Blood 2011, 117, 591– 594 DOI: 10.1182/blood-2010-03-275305
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- 101Highlights of Prescribing Information. Zydelig. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205858lbl.pdf (accessed June 12, 2016) .
- 102Benjamin, D.; Colombi, M.; Moroni, C.; Hall, M. H. Rapamycin passes the torch: a new generation of mTOR inhibitors Nat. Rev. Drug Discovery 2011, 10, 868– 880 DOI: 10.1038/nrd3531[Crossref], [PubMed], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlyis7vI&md5=a909649a82f3a2ce11c6b8fee78fa69eRapamycin passes the torch: a new generation of mTOR inhibitorsBenjamin, Don; Colombi, Marco; Moroni, Christoph; Hall, Michael N.Nature Reviews Drug Discovery (2011), 10 (11), 868-880CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Mammalian target of rapamycin (mTOR) is an atypical protein kinase that controls growth and metab. in response to nutrients, growth factors and cellular energy levels, and it is frequently dysregulated in cancer and metabolic disorders. Rapamycin is an allosteric inhibitor of mTOR, and was approved as an immuno-suppressant in 1999. In recent years, interest has focused on its potential as an anticancer drug. However, the performance of rapamycin and its analogs (rapalogues) has been undistinguished despite isolated successes in subsets of cancer, suggesting that the full therapeutic potential of targeting mTOR has yet to be exploited. A new generation of ATP-competitive inhibitors that directly target the mTOR catalytic site display potent and comprehensive mTOR inhibition and are in early clin. trials.
- 103Crowe, A.; Lemaire, M. In vitro and in situ absorption of SDZ-RAD using a human intestinal cell line (Caco-2) and a single pass perfusion model in rats: comparison with rapamycin Pharm. Res. 1998, 15, 1666– 1672 DOI: 10.1023/A:1011940108365
- 104Pike, K. G.; Malagu, K.; Hummersone, M. G.; Menear, K. A.; Duggan, H. M.; Gomez, S.; Martin, N. M.; Ruston, L.; Pass, S. L.; Pass, M. Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014 Bioorg. Med. Chem. Lett. 2013, 23, 1212– 1216 DOI: 10.1016/j.bmcl.2013.01.019[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFajs7c%253D&md5=325cb45f84bb4357005315ab3b27c0aaOptimization of potent and selective dual mTORC1 and mTORC2 inhibitors: The discovery of AZD8055 and AZD2014Pike, Kurt G.; Malagu, Karine; Hummersone, Marc G.; Menear, Keith A.; Duggan, Heather M. E.; Gomez, Sylvie; Martin, Niall M. B.; Ruston, Linette; Pass, Sarah L.; Pass, MartinBioorganic & Medicinal Chemistry Letters (2013), 23 (5), 1212-1216CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency while maintaining or improving other key parameters, such as aq. soly. and margins over hERG IC50, led to the discovery of the clin. candidate AZD8055. Further optimization, particularly aimed at reducing the rate of metab. in human hepatocyte incubations, resulted in the discovery of the clin. candidate AZD2014.
- 105Mortensen, D. S.; Perrin-Ninkovic, S. M.; Shevlin, G.; Zhao, J.; Packard, G.; Bahmanyar, S.; Correa, M.; Elsner, J.; Harris, R.; Lee, B. G. S.; Papa, P.; Parnes, J. S.; Riggs, J. R.; Sapienza, J.; Tehrani, L.; Whitefield, B.; Apuy, J.; Bisonette, R. R.; Gamez, J. C.; Hickman, M.; Khambatta, G.; Leisten, J.; Peng, S. X.; Richardson, S. J.; Cathers, B. E.; Canan, S. S.; Moghaddam, M. F.; Raymon, H. K.; Worland, P.; Narla, R. K.; Fultz, K. E.; Sankar, S. Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223 J. Med. Chem. 2015, 58, 5323– 5333 DOI: 10.1021/acs.jmedchem.5b00626[ACS Full Text], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVansrzI&md5=0f1ed6d929618ea8468fefefb196c606Discovery of Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor CC-223Mortensen, Deborah S.; Perrin-Ninkovic, Sophie M.; Shevlin, Graziella; Zhao, Jingjing; Packard, Garrick; Bahmanyar, Sogole; Correa, Matthew; Elsner, Jan; Harris, Roy; Lee, Branden G. S.; Papa, Patrick; Parnes, Jason S.; Riggs, Jennifer R.; Sapienza, John; Tehrani, Lida; Whitefield, Brandon; Apuy, Julius; Bisonette, Rene R.; Gamez, James C.; Hickman, Matt; Khambatta, Godrej; Leisten, Jim; Peng, Sophie X.; Richardson, Samantha J.; Cathers, Brian E.; Canan, Stacie S.; Moghaddam, Mehran F.; Raymon, Heather K.; Worland, Peter; Narla, Rama Krishna; Fultz, Kimberly E.; Sankar, SabitaJournal of Medicinal Chemistry (2015), 58 (13), 5323-5333CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compds. with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223, I, for clin. development.
- 106https://clinicaltrials.gov/ct2/show/NCT02619864 (accessed June 12, 2016) .
- 107Varga, A.; Mita, M. M.; Wu, J. J.; Nemunaitis, J. J.; Cloughesy, T. F.; Mischel, P. S.; Bendell, J. C.; Shih, K. C.; Paz-Ares, L. G.; Mahipal, A.; Delord, J.-P.; Kelley, R. K.; Soria, J.-C.; Wong, L.; Xu, S.; James, A.; Wu, X.; Chopra, R.; Hege, K.; Muster, P. N. Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid tumors J. Clin. Oncol. 2013, 31 (Suppl.) 2606
- 108Basu, B.; Dean, E.; Puglisi, M.; Greystoke, A.; Ong, M.; Burke, W.; Cavallin, M.; Bigley, G.; Womack, C.; Harrington, E. A.; Green, S.; Oelmann, E.; de Bono, J. S.; Ranson, M.; Banerji, U. First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor AZD2014 Clin. Cancer Res. 2015, 21, 3412– 3419 DOI: 10.1158/1078-0432.CCR-14-2422[Crossref], [PubMed], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1yqtrnN&md5=f5d4552e713519b1276135d56dbaf020First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014Basu, Bristi; Dean, Emma; Puglisi, Martina; Greystoke, Alastair; Ong, Michael; Burke, Wendy; Cavallin, Maria; Bigley, Graham; Womack, Christopher; Harrington, Elizabeth A.; Green, Stephen; Oelmann, Elisabeth; de Bono, Johann S.; Ranson, Malcolm; Banerji, UdaiClinical Cancer Research (2015), 21 (15), 3412-3419CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: AZD2014 is a novel, oral, m-TORC 1/2 inhibitor that has shown in vitro and in vivo efficacy across a range of preclin. human cancer models. Exptl. Design: A rolling six-dose escalation was performed to define an MTD (part A), and at MTD a further cohort of patients was treated to further characterize toxicities and perform pre- and posttreatment biopsies (part B). AZD2014 was administered orally twice a day continuously. Flow cytometry, ELISA, and immunohistochem. were used to quantify pharmacodynamic biomarkers. Pharmacokinetic anal. was carried out by mass spectrometry. Results: A total of 56 patients were treated across a dose range of 25 to 100 mg. The MTD was 50 mg twice daily. The dose-limiting toxicities were fatigue and mucositis. At the MTD, the most common adverse events (AE) were fatigue (78%), nausea (51%), and mucositis (49%), but these were equal to or greater than grade 3 in only 5% of patients. Drug levels achieved at the MTD (AUCss 6686 ng·h/mL, Cmax ss 1,664 ng/mL) were consistent with activity in preclin. models. A redn. in p-S6 levels and Ki67 staining was obsd. in 8 of 8 and 5 of 9 evaluable paired biopsy samples. Partial responses were seen in a patient with pancreatic cancer and a patient with breast cancer, who were found to have a PDGFR and ERBB2 mutation, resp. Conclusions: The recommended phase II dose for further evaluation of AZD2014 is 50 mg twice daily, and at this dose it has been possible to demonstrate pharmacol. relevant plasma concns., target inhibition in tumor, and clin. responses. Clin Cancer Res; 21(15); 3412-9. ©2015 AACR.
- 109Lin, F.; Buil, L.; Sherris, D.; Beijnen, J. H.; van Tellingen, O. Dual mTORC1 and mTORC2 inhibitor Palmoid 529 penetrates the blood-brain barrier without restriction by ABCB1 and ABCG2 Int. J. Cancer 2013, 133, 1222– 1234 DOI: 10.1002/ijc.28126[Crossref], [PubMed], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltVCjsb0%253D&md5=1f8450a5a09cf68eabd2b16227e1518bDual mTORC1 and mTORC2 inhibitor Palomid 529 penetrates the Blood-Brain Barrier without restriction by ABCB1 and ABCG2Lin, Fan; Buil, Levi; Sherris, David; Beijnen, Jos H.; Tellingen, OlafInternational Journal of Cancer (2013), 133 (5), 1222-1233CODEN: IJCNAW; ISSN:0020-7136. (John Wiley & Sons, Inc.)Palomid 529, a novel dual mTORC1/2 inhibitor has displayed interesting activities in exptl. models and is a candidate for clin. evaluation. We have assessed the interaction of Palomid 529 with ATP-binding cassette (ABC) drug efflux transporters ABCB1 (P-gp/P-glycoprotein) and ABCG2 (BCRP/Breast Cancer Resistant Protein) by in vitro transwell assays, and their effects on the brain penetration using drug disposition anal. of i.v. and oral Palomid 529 in wild-type (WT) and Abcb1 and/or Abcg2 knockout (KO) mice. Palomid 529 lacked affinity for these transporters in vitro, in contrast to GDC-0941, a small mol. PI3K inhibitor, which we used as control substance for in vitro transport. The plasma AUCi.v. of micronized and DMSO formulated Palomid 529 was similar in WT and KO mice. Importantly, the brain and brain tumor concn. of Palomid 529 at a high dose (54 mg/kg) was also similar in both strains, whereas a less than 1.4-fold difference (p < 0.05) was found at the low (5.4 mg/kg) dose. Because of poor soly., the oral bioavailability of micronized Palomid 529 was only 5%. Olive oil or spray-dried formulation greatly improved the bioavailability up to 50%. Finally, Palomid 529 effectively inhibits the orthotopic U87 glioblastoma growth. In summary, Palomid 529 is the first mTOR targeting drug lacking affinity for ABCB1/ABCG2 and having good brain penetration. This warrants further evaluation of Palomid 529 for treatment of high-grade gliomas and other intracranial malignancies.
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For AKT inhibitors that have entered clinical studies see the following:
(a) Pal, S. K.; Reckamp, K.; Yu, H.; Figlin, R. A. Akt inhibitors in clinical development for the treatment of cancer Expert Opin. Invest. Drugs 2010, 19, 1355– 1366 DOI: 10.1517/13543784.2010.520701(b) Rodon, J.; Dienstmann, R.; Serra, V.; Tabernero, J. Development of PI3K inhibitors: lessons learned from early clinical trials Nat. Rev. Clin. Oncol. 2013, 10, 143– 153 DOI: 10.1038/nrclinonc.2013.10[Crossref], [PubMed], [CAS], Google Scholar110bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsFGgs7w%253D&md5=cc6ef16605ed3f5f8619d6a1c7894d5cDevelopment of PI3K inhibitors: lessons learned from early clinical trialsRodon, Jordi; Dienstmann, Rodrigo; Serra, Violeta; Tabernero, JosepNature Reviews Clinical Oncology (2013), 10 (3), 143-153CODEN: NRCOAA; ISSN:1759-4774. (Nature Publishing Group)A review. The phosphatidylinositol 3-kinase (PI3K) pathway has an important role in cell metab., growth, migration, survival and angiogenesis. Drug development aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway has been fomented by observations that alterations in this pathway induce tumor formation and that inappropriate PI3K signalling is a frequent occurrence in human cancer. Many of the agents developed have been evaluated in early stage clin. trials. This Review focuses on early clin. and translational data related to inhibitors of the PI3K/AKT/mTOR pathway, as these data will likely guide the further clin. development of such agents. We review data from those trials, delineating the safety profile of the agents-whether obsd. sequelae could be mechanism-based or off-target effects-and drug efficacy. We describe predictive biomarkers explored in clin. trials and preclin. mechanisms of resistance. We also discuss key unresolved translational questions related to the clin. development of inhibitors of the PI3K/AKT/mTOR pathway and propose designs for biomarker-driven trials to address those issues. - 111Hilgard, P.; Klenner, T.; Stekar, J.; Nossner, G.; Kutscher, B.; Engel, J. D-21266, a new heterocyclic alkylphospholipid with antitumor activity Eur. J. Cancer 1997, 33, 442– 446 DOI: 10.1016/S0959-8049(97)89020-X
- 112Hirai, H.; Sootome, H.; Nakatsuru, Y.; Miyama, K.; Taguchi, S.; Tsujioka, K.; Ueno, Y.; Hatch, H.; Majumder, P. K.; Pan, B. S.; Kotani, H. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo Mol. Cancer Ther. 2010, 9, 1956– 1967 DOI: 10.1158/1535-7163.MCT-09-1012[Crossref], [PubMed], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFertbnL&md5=f2d97ab64963cc82d97b35697e49b172MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivoHirai, Hiroshi; Sootome, Hiroshi; Nakatsuru, Yoko; Miyama, Katsuyoshi; Taguchi, Shunsuke; Tsujioka, Kyoko; Ueno, Yoko; Hatch, Harold; Majumder, Pradip K.; Pan, Bo-Sheng; Kotani, HidehitoMolecular Cancer Therapeutics (2010), 9 (7), 1956-1967CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)The serine/threonine kinase Akt lies at a crit. signaling node downstream of phosphatidylinositol-3-kinase and is important in promoting cell survival and inhibiting apoptosis. An Akt inhibitor may be particularly useful for cancers in which increased Akt signaling is assocd. with reduced sensitivity to cytotoxic agents or receptor tyrosine kinase inhibitors. We evaluated the effect of a novel allosteric Akt inhibitor, MK-2206, in combination with several anticancer agents. In vitro, MK-2206 synergistically inhibited cell proliferation of human cancer cell lines in combination with mol. targeted agents such as erlotinib (an epidermal growth factor receptor inhibitor) or lapatinib (a dual epidermal growth factor receptor/human epidermal growth factor receptor 2 inhibitor). Complementary inhibition of erlotinib-insensitive Akt phosphorylation by MK-2206 was one mechanism of synergism, and a synergistic effect was found even in erlotinib-insensitive cell lines. MK-2206 also showed synergistic responses in combination with cytotoxic agents such as topoisomerase inhibitors (doxorubicin, camptothecin), antimetabolites (gemcitabine, 5-fluorouracil), anti-microtubule agents (docetaxel), and DNA cross-linkers (carboplatin) in lung NCI-H460 or ovarian A2780 tumor cells. The synergy with docetaxel depended on the treatment sequence; a schedule of MK-2206 dosed before docetaxel was not effective. MK-2206 suppressed the Akt phosphorylation that is induced by carboplatin and gemcitabine. In vivo, MK-2206 in combination with these agents exerted significantly more potent tumor inhibitory activities than each agent in the monotherapy setting. These findings suggest that Akt inhibition may augment the efficacy of existing cancer therapeutics; thus, MK-2206 is a promising agent to treat cancer patients who receive these cytotoxic and/or mol. targeted agents.
- 113Dunn, D. E.; He, D. N.; Yang, P.; Johansen, M.; Newman, R. A.; Lo, D. C. In vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke models J. Neurochem. 2011, 119, 805– 814 DOI: 10.1111/j.1471-4159.2011.07439.x[Crossref], [PubMed], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVGqsrrP&md5=6f77667e0bf5962040c6ecac0ffd5f7bIn vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke modelsDunn, Denise E.; He, Dong Ning; Yang, Peiying; Johansen, Mary; Newman, Robert A.; Lo, Donald C.Journal of Neurochemistry (2011), 119 (3 & 4), 805-814CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)The principal active constituent of the botanical drug candidate PBI-05204, a supercrit. CO2 ext. of Nerium oleander, is the cardiac glycoside oleandrin. PBI-05204 shows potent anticancer activity and is currently in phase I clin. trial as a treatment for patients with solid tumors. We have previously shown that neriifolin, which is structurally related to oleandrin, provides robust neuroprotection in brain slice and whole animal models of ischemic injury. However, neriifolin itself is not a suitable drug development candidate and the FDA-approved cardiac glycoside digoxin does not cross the blood-brain barrier. We report here that both oleandrin as well as the full PBI-05204 ext. can also provide significant neuroprotection to neural tissues damaged by oxygen and glucose deprivation as occurs in ischemic stroke. Critically, we show that the neuroprotective activity of PBI-05204 is maintained for several hours of delay of administration after oxygen and glucose deprivation treatment. We provide evidence that the neuroprotective activity of PBI-05204 is mediated through oleandrin and/or other cardiac glycoside constituents, but that addnl., non-cardiac glycoside components of PBI-05204 may also contribute to the obsd. neuroprotective activity. Finally, we show directly that both oleandrin and the protective activity of PBI-05204 are blood brain barrier penetrant in a novel model for in vivo neuroprotection. Together, these findings suggest clin. potential for PBI-05204 in the treatment of ischemic stroke and prevention of assocd. neuronal death.
- 114Heerding, D. A.; Rhodes, N.; Leber, J. D.; Clark, T. J.; Keenan, R. M.; Lafrance, L. V.; Li, M.; Safonov, I. G.; Takata, D. T.; Venslavsky, J. W.; Yamashita, D. S.; Choudhry, A. E.; Copeland, R. A.; Lai, Z.; Schaber, M. D.; Tummino, P. J.; Strum, S. L.; Wood, E. R.; Duckett, D. R.; Eberwein, D.; Knick, V. B.; Lansing, T. J.; McConnell, R. T.; Zhang, S.; Minthorn, E. A.; Concha, N. O.; Warren, G. L.; Kumar, R. Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase J. Med. Chem. 2008, 51, 5663– 5679 DOI: 10.1021/jm8004527[ACS Full Text], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVChs7bE&md5=c0e6f283a3ee79dffafdd90ec69513bcIdentification of 4-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a Novel Inhibitor of AKT KinaseHeerding, Dirk A.; Rhodes, Nelson; Leber, Jack D.; Clark, Tammy J.; Keenan, Richard M.; Lafrance, Louis V.; Li, Mei; Safonov, Igor G.; Takata, Dennis T.; Venslavsky, Joseph W.; Yamashita, Dennis S.; Choudhry, Anthony E.; Copeland, Robert A.; Lai, Zhihong; Schaber, Michael D.; Tummino, Peter J.; Strum, Susan L.; Wood, Edgar R.; Duckett, Derek R.; Eberwein, Derek; Knick, Victoria B.; Lansing, Timothy J.; McConnell, Randy T.; Zhang, Shu Yun; Minthorn, Elisabeth A.; Concha, Nestor O.; Warren, Gregory L.; Kumar, RakeshJournal of Medicinal Chemistry (2008), 51 (18), 5663-5679CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant neg. AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compd. 3g (GSK690693, I). Compd. 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC50 values of 2, 13, and 9 nM against AKT1, 2, and 3, resp. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compd. 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3β. I.p. administration of 3g in immunocompromised mice results in the inhibition of GSK3β phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.
- 115Dumble, M.; Crouthamel, M.; Zhang, S.; Schaber, M.; Levy, D.; Robell, K.; Liu, Q.; Figueroa, D. J.; Minthorn, E. A.; Seefeld, M. A.; Rouse, M. B.; Rabindran, S. K.; Heerding, D. A.; Kumar, R. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor PLoS One 2014, 9, e100880 DOI: 10.1371/journal.pone.0100880[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1emur3K&md5=893494388f4f390ae5a6bc3d30114c89Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitorDumble, Melissa; Crouthamel, Ming-Chih; Zhang, Shu-Yun; Schaber, Michael; Levy, Dana; Robell, Kimberly; Liu, Qi; Figueroa, David J.; Minthorn, Elisabeth A.; Seefeld, Mark A.; Rouse, Meagan B.; Rabindran, Sridhar K.; Heerding, Dirk A.; Kumar, RakeshPLoS One (2014), 9 (6), e100880/1-e100880/11, 11 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clin. studies. Both compds. are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compd. show decreased phosphorylation of several substrates downstream of AKT. Both compds. have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histol. origins. Improved kinase selectivity was assocd. with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater redn. in phospho-S6 levels. Taken together these results support clin. evaluation of the AKT inhibitors in cancer, esp. in combination with MEK inhibitor.
- 116Blake, J. F.; Xu, R.; Bencsik, J. R.; Xiao, D.; Kallan, N. C.; Schlachter, S.; Mitchell, I. S.; Spencer, K. L.; Banka, A. L.; Wallace, E. M.; Gloor, S. L.; Martinson, M.; Woessner, R. D.; Vigers, G. P.; Brandhuber, B. J.; Liang, J.; Safina, B. S.; Li, J.; Zhang, B.; Chabot, C.; Do, S.; Lee, L.; Oeh, J.; Sampath, D.; Lee, B. B.; Lin, K.; Liederer, B. M.; Skelton, N. J. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors J. Med. Chem. 2012, 55, 8110– 8127 DOI: 10.1021/jm301024w[ACS Full Text], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1yrtr7K&md5=1fa690cda22a2548eb2795305e1c7253Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human TumorsBlake, James F.; Xu, Rui; Bencsik, Josef R.; Xiao, Dengming; Kallan, Nicholas C.; Schlachter, Stephen; Mitchell, Ian S.; Spencer, Keith L.; Banka, Anna L.; Wallace, Eli M.; Gloor, Susan L.; Martinson, Matthew; Woessner, Richard D.; Vigers, Guy P. A.; Brandhuber, Barbara J.; Liang, Jun; Safina, Brian S.; Li, Jun; Zhang, Birong; Chabot, Christine; Do, Steven; Lee, Leslie; Oeh, Jason; Sampath, Deepak; Lee, Brian B.; Lin, Kui; Liederer, Bianca M.; Skelton, Nicholas J.Journal of Medicinal Chemistry (2012), 55 (18), 8110-8127CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compds. that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compds. demonstrate potent inhibition of all three Akt isoforms in biochem. assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biol. studies with one such compd., 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clin. trials for the treatment of cancer.
- 117Lapierre, J.-M.; Eathiraj, S.; Vensel, D.; Liu, Y.; Bull, C. O.; Cornell-Kennon, S.; Iimura, S.; Kelleher, E. W.; Kizer, D. E.; Koerner, S.; Makhija, S.; Matsuda, A.; Moussa, M.; Namdev, N.; Savage, R. E.; Szwaya, J.; Volckova, E.; Westlund, N.; Wu, H.; Schwartz, B. Discovery of 3-(3-(4-(1-aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): an orally bioavailable, selective, and potent allosteric AKT inhibitor J. Med. Chem. 2016, 59, 6455– 6469 DOI: 10.1021/acs.jmedchem.6b00619[ACS Full Text], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpvFygtrg%253D&md5=fb29dbafd5fdd28e0e500f57e42cd42dDiscovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT InhibitorLapierre, Jean-Marc; Eathiraj, Sudharshan; Vensel, David; Liu, Yanbin; Bull, Cathy O.; Cornell-Kennon, Susan; Iimura, Shin; Kelleher, Eugene W.; Kizer, Darin E.; Koerner, Steffi; Makhija, Sapna; Matsuda, Akihisa; Moussa, Magdi; Namdev, Nivedita; Savage, Ronald E.; Szwaya, Jeff; Volckova, Erika; Westlund, Neil; Wu, Hui; Schwartz, BrianJournal of Medicinal Chemistry (2016), 59 (13), 6455-6469CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chem. series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compd. 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chem. class and the role of the cyclobutylamine moiety. Compd. 21a demonstrated high enzymic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compd. 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.
- 118Vink, S. R.; Schellens, J. H.; van Blitterswijk, W. J.; Verheij, M. Tumor and normal tissue pharmacokinetics of perifosine, an oral anti-cancer alkylphospholipid Invest. New Drugs 2005, 23, 279– 286 DOI: 10.1007/s10637-005-1436-0
- 119Dunn, D. E.; He, D. N.; Yang, P.; Johansen, M.; Newman, R. A.; Lo, D. C. In vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke models J. Neurochem. 2011, 119, 805– 814 DOI: 10.1111/j.1471-4159.2011.07439.x[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVGqsrrP&md5=6f77667e0bf5962040c6ecac0ffd5f7bIn vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke modelsDunn, Denise E.; He, Dong Ning; Yang, Peiying; Johansen, Mary; Newman, Robert A.; Lo, Donald C.Journal of Neurochemistry (2011), 119 (3 & 4), 805-814CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)The principal active constituent of the botanical drug candidate PBI-05204, a supercrit. CO2 ext. of Nerium oleander, is the cardiac glycoside oleandrin. PBI-05204 shows potent anticancer activity and is currently in phase I clin. trial as a treatment for patients with solid tumors. We have previously shown that neriifolin, which is structurally related to oleandrin, provides robust neuroprotection in brain slice and whole animal models of ischemic injury. However, neriifolin itself is not a suitable drug development candidate and the FDA-approved cardiac glycoside digoxin does not cross the blood-brain barrier. We report here that both oleandrin as well as the full PBI-05204 ext. can also provide significant neuroprotection to neural tissues damaged by oxygen and glucose deprivation as occurs in ischemic stroke. Critically, we show that the neuroprotective activity of PBI-05204 is maintained for several hours of delay of administration after oxygen and glucose deprivation treatment. We provide evidence that the neuroprotective activity of PBI-05204 is mediated through oleandrin and/or other cardiac glycoside constituents, but that addnl., non-cardiac glycoside components of PBI-05204 may also contribute to the obsd. neuroprotective activity. Finally, we show directly that both oleandrin and the protective activity of PBI-05204 are blood brain barrier penetrant in a novel model for in vivo neuroprotection. Together, these findings suggest clin. potential for PBI-05204 in the treatment of ischemic stroke and prevention of assocd. neuronal death.
- 120Newton, H. B. Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors Expert Rev. Anticancer Ther. 2003, 3, 595– 614 DOI: 10.1586/14737140.3.5.595[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpt1arsLc%253D&md5=313ecd065623c60f3dab2c2cb3ec91a6Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: growth factor and Ras signaling pathwaysNewton, Herbert B.Expert Review of Anticancer Therapy (2003), 3 (5), 595-614CODEN: ERATBJ; ISSN:1473-7140. (Future Drugs Ltd.)A review. Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Mol. neuro-oncol. has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that may be amenable to targeted therapy. Growth factor signaling pathways are often upregulated in brain tumors and may contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the Ras signaling pathway, which is frequently aberrant in brain tumors. Receptor tyrosine kinase inhibitors, antireceptor monoclonal antibodies and antisense oligonucleotides are targeted approaches under investigation as methods to regulate aberrant growth factor signaling pathways in brain tumors. Several receptor tyrosine kinase inhibitors, including imatinib mesylate (Gleevec), gefitinib (Iressa) and erlotinib (Tarceva), have entered clin. trials for high-grade glioma patients. Farnesyl transferase inhibitors, such as tipifarnib (Zarnestra), which impair processing of proRas and inhibit the Ras signaling pathway, have also entered clin. trials for patients with malignant gliomas. Further development of targeted therapies and evaluation of these new agents in clin. trials will be needed to improve survival and quality of life of patients with brain tumors.
- 121Singh, D.; Chan, J. M.; Zoppoli, P.; Niola, F.; Sullivan, R.; Castano, A.; Liu, E. M.; Reichel, J.; Porrati, P.; Pellegatta, S.; Qiu, K.; Gao, Z.; Ceccarelli, M.; Riccardi, R.; Brat, D. J.; Guha, A.; Aldape, K.; Golfinos, J. G.; Zagzag, D.; Mikkelsen, T.; Finocchiaro, G.; Lasorella, A.; Rabadan, R.; Iavarone, A. Transofrming fusions of FGFR and TACC genes in human glioblastoma Science 2012, 337, 1231– 1235 DOI: 10.1126/science.1220834
- 122(a) Shaw, A. T.; Hsu, P. P.; Awad, M. M.; Engleman, J. A. Tyrosine kinase gene rearrangements in epithelial malignancies Nat. Rev. Cancer 2013, 13, 772– 787 DOI: 10.1038/nrc3612[Crossref], [PubMed], [CAS], Google Scholar122ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1ertrjE&md5=ffb14b30706c8d935392647900b2e8c9Tyrosine kinase gene rearrangements in epithelial malignanciesShaw, Alice T.; Hsu, Peggy P.; Awad, Mark M.; Engelman, Jeffrey A.Nature Reviews Cancer (2013), 13 (11), 772-787CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. Chromosomal rearrangements that lead to oncogenic kinase activation are obsd. in many epithelial cancers. These cancers express activated fusion kinases that drive the initiation and progression of malignancy, and often have a considerable response to small-mol. kinase inhibitors, which validates these fusion kinases as 'druggable' targets. In this Review, we examine the etiol., pathogenic and clin. features that are assocd. with cancers harbouring oncogenic fusion kinases, including anaplastic lymphoma kinase (ALK), ROS1 and RET. We discuss the clin. outcomes with targeted therapies and explore strategies to discover addnl. kinases that are activated by chromosomal rearrangements in solid tumors.(b) Dieci, M. V.; Arnedos, M.; Andre, F.; Soria, J. C. Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives Cancer Discovery 2013, 3, 264– 279 DOI: 10.1158/2159-8290.CD-12-0362[Crossref], [PubMed], [CAS], Google Scholar122bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltVOktL4%253D&md5=0e694a7641aa83c1540f745576f04bfaFibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical PerspectivesDieci, Maria Vittoria; Arnedos, Monica; Andre, Fabrice; Soria, Jean CharlesCancer Discovery (2013), 3 (3), 264-279CODEN: CDAIB2; ISSN:2159-8274. (American Association for Cancer Research)A review. The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiol. processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifications, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, class-specific toxicity profiles and correctly designing clin. trials to address these different issues. Significance: FGF/FGFR pathway deregulations are increasingly recognized across different human cancers. Understanding the mechanisms at the basis of these alterations and their multiple roles in cancer promotion and drug resistance is a fundamental step for further implementation of targeted therapies and research strategies.
- 123Brooks, A. N.; Kilgour, E.; Smith, P. D. Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer Clin. Cancer Res. 2012, 18, 1855– 1862 DOI: 10.1158/1078-0432.CCR-11-0699[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkvFOmurk%253D&md5=a355aee7dc1b310177c6165b43896b75Molecular Pathways: Fibroblast Growth Factor Signaling: A New Therapeutic Opportunity in CancerBrooks, A. Nigel; Kilgour, Elaine; Smith, Paul D.Clinical Cancer Research (2012), 18 (7), 1855-1862CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)A review. The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling axis plays an important role in normal organ, vascular, and skeletal development. Deregulation of FGFR signaling through genetic modification or overexpression of the receptors (or their ligands) has been obsd. in numerous tumor settings, whereas the FGF/FGFR axis also plays a key role in driving tumor angiogenesis. A growing body of preclin. data shows that inhibition of FGFR signaling can result in antiproliferative and/or proapoptotic effects, both in vitro and in vivo, thus confirming the validity of the FGF/FGFR axis as a potential therapeutic target. In the past, development of therapeutic approaches to target this axis has been hampered by our inability to develop FGFR-selective agents. With the advent of a no. of new modalities for selectively inhibiting FGF/FGFR signaling, we are now in a unique position to test and validate clin. the many hypotheses that have been generated preclinically. Clin Cancer Res; 18(7); 1855-62.
- 124Gavine, P. R.; Mooney, L.; Kilgour, E.; Thomas, A. P.; Al-Kadhimi, K.; Beck, S.; Rooney, C.; Coleman, T.; Baker, D.; Mellor, M. J.; Brooks, A. N.; Klinowska, T. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family Cancer Res. 2012, 72, 2045– 2056 DOI: 10.1158/0008-5472.CAN-11-3034[Crossref], [PubMed], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xls1Wgsrs%253D&md5=cba90ad8f9b9e51cd10288868bbcc85eAZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase FamilyGavine, Paul R.; Mooney, Lorraine; Kilgour, Elaine; Thomas, Andrew P.; Al-Kadhimi, Katherine; Beck, Sarah; Rooney, Claire; Coleman, Tanya; Baker, Dawn; Mellor, Martine J.; Brooks, A. Nigel; Klinowska, TeresaCancer Research (2012), 72 (8), 2045-2056CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The fibroblast growth factor (FGF) signaling axis is increasingly implicated in tumorigenesis and chemoresistance. Several small-mol. FGF receptor (FGFR) kinase inhibitors are currently in clin. development; however, the predominant activity of the most advanced of these agents is against the kinase insert domain receptor (KDR), which compromises the FGFR selectivity. Here, we report the pharmacol. profile of AZD4547, a novel and selective inhibitor of the FGFR1, 2, and 3 tyrosine kinases. AZD4547 inhibited recombinant FGFR kinase activity in vitro and suppressed FGFR signaling and growth in tumor cell lines with deregulated FGFR expression. In a representative FGFR-driven human tumor xenograft model, oral administration of AZD4547 was well tolerated and resulted in potent dose-dependent antitumor activity, consistent with plasma exposure and pharmacodynamic modulation of tumor FGFR. Importantly, at efficacious doses, no evidence of anti-KDR-related effects were obsd., confirming the in vivo FGFR selectivity of AZD4547. Taken together, our findings show that AZD4547 is a novel selective small-mol. inhibitor of FGFR with potent antitumor activity against FGFR-deregulated tumors in preclin. models. AZD4547 is under clin. investigation for the treatment of FGFR-dependent tumors. Cancer Res; 72(8); 2045-56.
- 125Guagnano, V.; Furet, P.; Spanka, C.; Bordas, V.; Le Douget, M.; Stamm, C.; Brueggen, J.; Jensen, M. R.; Schnell, C.; Schmid, H.; Wartmann, M.; Berghausen, J.; Drueckes, P.; Zimmerlin, A.; Bussiere, D.; Murray, J.; Graus Porta, D. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase J. Med. Chem. 2011, 54, 7066– 7083 DOI: 10.1021/jm2006222[ACS Full Text], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1SrsrvK&md5=f9a2d742294cd3814e872bdd8add1ffaDiscovery of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), A Potent and Selective Inhibitor of the Fibroblast Growth Factor Receptor Family of Receptor Tyrosine KinaseGuagnano, Vito; Furet, Pascal; Spanka, Carsten; Bordas, Vincent; Le Douget, Mickael; Stamm, Christelle; Brueggen, Josef; Jensen, Michael R.; Schnell, Christian; Schmid, Herbert; Wartmann, Markus; Berghausen, Joerg; Drueckes, Peter; Zimmerlin, Alfred; Bussiere, Dirksen; Murray, Jeremy; Graus Porta, DianaJournal of Medicinal Chemistry (2011), 54 (20), 7066-7083CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the basis of its in vitro profile, compd. 1h (NVP-BGJ398) was selected for in vivo evaluation and showed significant antitumor activity in RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support the potential therapeutic use of 1h as a new anticancer agent.
- 126Angibaud, P. R.; Mevellec, L.; Saxty, G.; Adelinet, C.; Akkari, R.; Berdini, V.; Bonnet, P.; Bourgeois, M.; Bourdrez, X.; Cleasby, A.; Colombel, H.; Csoka, I.; Embrechts, W.; Freyne, E.; Gilissen, R.; Jovcheva, E.; King, P.; Lacrampe, J.; Lardeau, D.; Ligny, Y.; Mcclue, S.; Meerpoel, L.; Newell, D. R.; Page, M.; Papanikos, A.; Pasquier, E.; Pilatte, I.; Poncelet, V.; Querolle, O.; Rees, D. C.; Rich, S.; Roux, B.; Sement, E.; Simonnet, Y.; Squires, M.; Tronel, V.; Verhulst, T.; Vialard, J.; Willems, M.; Woodhead, S. J.; Wroblowski, B.; Murray, C. W.; Perera, T. Abstract 4748: Discovery of JNJ-42756493, a potent fibroblast growth factor receptor (FGFR) inhibitor using a fragment based approach Cancer Res. 2014, 74 (Suppl.) 4748 DOI: 10.1158/1538-7445.AM2014-4748
- 127Nakanishi, Y.; Akiyama, N.; Tsukaguchi, T.; Fujii, T.; Sakata, K.; Sase, H.; Isobe, T.; Morikami, K.; Shindoh, H.; Mio, T.; Ebiike, H.; Taka; Naoki, N.; Aoki, Y.; Ishii, N. The fibroblast growth factor receptor genetic status as a potential predictor for the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor Mol. Cancer Ther. 2014, 13, 2547– 2558 DOI: 10.1158/1535-7163.MCT-14-0248[Crossref], [PubMed], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVGju73F&md5=35629d891a421582022b0f6ae0496479The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR InhibitorNakanishi, Yoshito; Akiyama, Nukinori; Tsukaguchi, Toshiyuki; Fujii, Toshihiko; Sakata, Kiyoaki; Sase, Hitoshi; Isobe, Takehito; Morikami, Kenji; Shindoh, Hidetoshi; Mio, Toshiyuki; Ebiike, Hirosato; Taka, Naoki; Aoki, Yuko; Ishii, NobuyaMolecular Cancer Therapeutics (2014), 13 (11), 2547-2558CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-mol. inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family displayed clin. benefits in cohorts of patients with FGFR genetic alterations. However, to achieve more potent and prolonged activity in such populations, a selective FGFR inhibitor is still needed. Here, we report the identification of CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chem. scaffold. By interacting with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 displayed preferential antitumor activity against cancer cells with various FGFR genetic alterations in a panel of 327 cancer cell lines and in xenograft models. Because of its unique binding mode, CH5183284/Debio 1347 can inhibit FGFR2 harboring one type of the gatekeeper mutation that causes resistance to other FGFR inhibitors and block FGFR2 V564F-driven tumor growth. CH5183284/Debio 1347 is under clin. investigation for the treatment of patients harboring FGFR genetic alterations. Mol Cancer Ther; 13(11); 2547-58. ©2014 AACR.
- 128https://clinicaltrials.gov/ct2/show/NCT01975701 (accessed June 12, 2016) .
- 129Savage, R. E.; Hall, T.; Schwartz, B. ARQ 087, a novel pan FGFR-inhibitor crosses the BBB (blood brain barrier) and distributes to the brain of rats Eur. J. Cancer 2014, 50 (Suppl. 6) 50 DOI: 10.1016/S0959-8049(14)70271-0
- 130Elmlinger, M. W.; Deininger, M. H.; Schuett, B. S.; Meyermann, R.; Duffner, F.; Grote, E. H.; Ranke, M. B. In vivo expression of insulin-like growth factor-binding protein-2 in human gliomas increases with the tumor grade Endocrinology 2001, 142, 1652– 1658 DOI: 10.1210/endo.142.4.8084
- 131Chen, H. X.; Sharon, E. IGF-1R as an anti-cancer target—trials and tribulations Aizheng 2013, 32, 242– 252 DOI: 10.5732/cjc.012.10263[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVeltr3I&md5=5534aa8d4dbfefe5dd2e5248be888328IGF-1R as an anti-cancer target-trials and tribulationsChen, Helen X.; Sharon, EladChinese Journal of Cancer (2013), 32 (5), 242-252CODEN: CJCHDJ ISSN:. (Sun Yat-sen University Cancer Center)A review. Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clin. trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF-2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R-targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacol. features. Clin. activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small no. of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clin. trials involving patients with adult tumors, including non-small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clin. benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be crit. to success in future development.
- 132Mulvihill, M. J.; Cooke, A.; Rosenfeld-Franklin, M.; Buck, E.; Foreman, K.; Landfair, D.; O’Connor, M.; Pirritt, C.; Sun, Y.; Yao, Y.; Arnold, L. D.; Gibson, N. W.; Ji, Q. S. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-I receptor and insulin receptor Future Med. Chem. 2009, 1, 1153– 1171 DOI: 10.4155/fmc.09.89[Crossref], [PubMed], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVChs7zM&md5=c7583de9d57e3af55ff2fa0c3708fd93Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-I receptor and insulin receptorMulvihill, Mark J.; Cooke, Andrew; Rosenfeld-Franklin, Maryland; Buck, Elizabeth; Foreman, Ken; Landfair, Darla; O'Connor, Matthew; Pirritt, Caroline; Sun, Yingchaun; Yao, Yan; Arnold, Lee D.; Gibson, Neil W.; Ji, Qun-ShengFuture Medicinal Chemistry (2009), 1 (6), 1153-1171CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)The IGF-I receptor (IGF-IR) has been implicated in the promotion of tumorigenesis, metastasis and resistance to cancer therapies. Therefore, this receptor has become a major focus for the development of anticancer agents. Our lead optimization efforts that blended structure-based design and empirical medicinal chem. led to the discovery of OSI-906, a novel small-mol. dual IGF-IR/insulin receptor (IR) kinase inhibitor. OSI-906 potently and selectively inhibits autophosphorylation of both human IGF-IR and IR, displays in vitro antiproliferative effects in a variety of tumor cell lines and shows robust in vivo anti-tumor efficacy in an IGF-IR-driven xenograft model when administered orally once daily. OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-IR/IR kinase inhibitor with favorable preclin. drug-like properties, which has demonstrated in vivo efficacy in tumor models and is currently in clin. testing.
- 133Carboni, J. M.; Wittman, M.; Yang, Z.; Lee, F.; Greer, A.; Hurlburt, W.; Hillerman, S.; Cao, C.; Cantor, G. H.; Dell-John, J.; Chen, C.; Discenza, L.; Menard, K.; Li, A.; Trainor, G.; Vyas, D.; Kramer, R.; Attar, R. M.; Gottardis, M. M. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR Mol. Cancer Ther. 2009, 8, 3341– 3349 DOI: 10.1158/1535-7163.MCT-09-0499[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFCitb3F&md5=1f348da6d076373aaf9296ebfcfc5542BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IRCarboni, Joan M.; Wittman, Mark; Yang, Zheng; Lee, Francis; Greer, Ann; Hurlburt, Warren; Hillerman, Stephen; Cao, Carolyn; Cantor, Glenn H.; Dell-John, Janet; Chen, Cliff; Discenza, Lorell; Menard, Krista; Li, Aixin; Trainor, George; Vyas, Dolatrai; Kramer, Robert; Attar, Ricardo M.; Gottardis, Marco M.Molecular Cancer Therapeutics (2009), 8 (12), 3341-3349CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compd. caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a min. ED of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clin. outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.
- 134Vasilcanu, D.; Girnita, A.; Girnita, L.; Vasilcanu, R.; Axelson, A.; Larsson, O. The cyclolignan PPP induces activation loop-specific inhibition of tyrosine phosphorylation of the insulin-like growth factor-1 receptor. Link to the phosphatidyl inositol-3 kinase/Akt apoptotic pathway Oncogene 2004, 23, 7854– 7862 DOI: 10.1038/sj.onc.1208065
- 135Guz, N. R.; Leuser, H.; Goldman, E. Process development and multikilogram syntheses of XL228 utilizing a regioselective isoxazole formation and a selective SNAr reaction to a pyrimidine core Org. Process Res. Dev. 2013, 17, 1066– 1073 DOI: 10.1021/op400137m
- 136Rodon, J.; De Santos, V.; Ferry, R. J.; Kurzrock, R. Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials Mol. Cancer Ther. 2008, 7, 2575– 2588 DOI: 10.1158/1535-7163.MCT-08-0265[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFSms7jJ&md5=d37e37d3752231ef2c152110c1e85a66Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: Lessons from the first clinical trialsRodon, Jordi; De Santos, Victoria; Ferry, Robert Jean, Jr.; Kurzrock, RazelleMolecular Cancer Therapeutics (2008), 7 (9), 2575-2588CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)A review. The insulin-like growth factor-I receptor (IGF-IR) was first cloned in 1986. Since then, intense work has defined classic phosphorelays activated via the IGF-IR, which regulate cell proliferation, apoptosis, motility, and fate. The understanding of the roles of hormones in cancer and the growth hormone-IGF-IGF-binding protein axis specifically has yield to a second wave of development: the design of specific inhibitors that interrupt the signaling assocd. with this axis. The ability to manipulate these pathways holds not only significant therapeutic implications but also increase the chance of deeper insight about the role of the axis in carcinogenesis and metastasis. Nowadays, >25 mols. with the same goal are at different stages of development. Here, we review the clin. and preclin. experience with the two most-investigated strategies, tyrosine kinase inhibitors and monoclonal antibodies, and the advantages and disadvantages of each strategy, as well as other alternatives and possible drug combinations. We also review the biomarkers explored in the first clin. trials, the strategies that have been explored thus far, and the clin. trials that are going to explore their role in cancer treatment.
- 137Halvorson, K. G.; Barton, K. L.; Schroeder, K.; Misuraca, K. L.; Hoeman, C.; Chung, A.; Crabtree, D. M.; Cordero, F. J.; Singh, R.; Spasojevic, I.; Berlow, N.; Pal, R.; Becher, O. J. A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent PLoS One 2015, 10, e0118926 DOI: 10.1371/journal.pone.0118926
- 138Boston-Howes, W.; Williams, E. O.; Bogush, A.; Scolere, M.; Pasinelli, P.; Trotti, D. Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: therapeutic implications for amyotrophic lateral sclerosis Exp. Neurol. 2008, 213, 229– 237 DOI: 10.1016/j.expneurol.2008.06.010[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVSgurbK&md5=234cf9e059cef90a66c4cea69a656195Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: Therapeutic implications for amyotrophic lateral sclerosisBoston-Howes, William; Williams, Eric O.; Bogush, Alexey; Scolere, Maura; Pasinelli, Piera; Trotti, DavideExperimental Neurology (2008), 213 (1), 229-237CODEN: EXNEAC; ISSN:0014-4886. (Elsevier Inc.)Synaptic accumulation of glutamate causes neuronal death in many neurodegenerative pathologies including amyotrophic lateral sclerosis. Drugs capable of increasing glutamate uptake could therefore be therapeutically effective. We screened in a cell-based assay a library of 1040 FDA-approved drugs and nutrients for compds. that could enhance glutamate uptake. Nordihydroguaiaretic acid (NDGA), an anti-inflammatory drug that inhibits lipoxygensases, potently enhanced glutamate uptake in MN-1 cells. Given s.c. at 1 mg/day for 30 days in mice, NDGA increased glutamate uptake in spinal cord synaptosomes persistently throughout the treatment. However, when administered following the same regimen to the SOD1-G93A transgenic mouse model of ALS at disease onset, NDGA did not extend survival of these mice. We found that NDGA failed to sustain increased glutamate uptake in the SOD1-G93A mice despite an initial upregulation measured during the first 10 days of treatment. SOD1-G93A mice displayed a progressive increase in spinal cord expression levels of the efflux transporter P-glycoprotein beginning at disease onset. This increase was not mediated by the NDGA treatment because it was measured in untreated SOD1-G93A mice. Since P-glycoproteins control the extrusion of a broad range of toxins and xenobiotics and are responsible for drug resistance in many diseases including cancer and brain diseases such as epilepsy, we propose that the failure of NDGA in maintaining glutamate uptake upregulated in SOD1-G93A mice and its therapeutic inefficacy are due to acquired pharmacoresistance mediated by the increased expression of P-glycoprotein.
- 139Parsons, D. W.; Jones, S.; Zhang, X.; Lin, J. C.-H.; Leary, R. J.; Angenendt, P.; Mankoo, P.; Carter, H.; Siu, I.-M.; Gallia, G. L.; Olivi, A.; McLendon, R.; Rasheed, B. A.; Keir, S.; Nikolskaya, T.; Nikolsky, Y.; Busam, D. A.; Tekleab, H.; Diaz, L. A.; Hartigan, J.; Smith, D. R.; Strausberg, R. L.; Marie, S. K. N.; Shinjo, S. M. O.; Yan, H.; Riggins, G. J.; Bigner, D. D.; Karchin, R.; Papadopoulos, N.; Parmiqiani, G.; Vogelstein, B.; Velculescu, V. E.; Kinzler, K. W. An integrated genomic analysis of human glioblastoma multiforme Science 2008, 321, 1807– 1812 DOI: 10.1126/science.1164382[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFCrtLrE&md5=88c9e87c4b9dc8ebedcaa2b5d9f3ce13An Integrated genomic analysis of human glioblastoma multiformeParsons, D. Williams; Jones, Sian; Zhang, Xiaosong; Lin, Jimmy Cheng-Ho; Leary, Rebecca J.; Angenendt, Philipp; Mankoo, Parminder; Carter, Hannah; Siu, I.-Mei; Gallia, Gary L.; Olivi, Alessandro; McLendon, Roger; Rasheed, B. Ahmed; Keir, Stephen; Nikolskaya, Tatiana; Nikolsky, Yuri; Busam, Dana A.; Tekleab, Hanna; Diaz, Luis A., Jr.; Hartigan, James; Smith, Doug R.; Strausberg, Robert L.; Marie, Suely Kazue Nagahashi; Shinjo, Sueli Mieko Oba; Yan, Hai; Riggins, Gregory J.; Bigner, Darell D.; Karchin, Rachel; Papadopoulos, Nick; Parmigiani, Giovanni; Vogelstein, Bert; Velculescu, Victor E.; Kinzler, Kenneth W.Science (Washington, DC, United States) (2008), 321 (5897), 1807-1812CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)A review based on author's research. Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, detd. the presence of amplifications and deletions using high-d. oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive anal. led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were assocd. with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.
- 140(a) Paugh, B. S.; Broniscer, A.; Qu, C.; Miller, C. P.; Zhang, J.; Tatevossian, R. G.; Olson, J. M.; Geyer, J. R.; Chi, S. N.; da Silva, N. S.; Onar-Thomas, A.; Baker, J. N.; Gajjar, A.; Ellison, D. W.; Baker, Z. J. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma J. Clin. Oncol. 2011, 29, 3999– 4006 DOI: 10.1200/JCO.2011.35.5677[Crossref], [PubMed], [CAS], Google Scholar140ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFams7bP&md5=f7c34fb55df46d685514103b4c66fb06Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine gliomaPaugh, Barbara S.; Broniscer, Alberto; Qu, Chunxu; Miller, Claudia P.; Zhang, Junyuan; Tatevossian, Ruth G.; Olson, James M.; Geyer, J. Russell; Chi, Susan N.; Saba da Silva, Nasjla; Onar-Thomas, Arzu; Baker, Justin N.; Gajjar, Amar; Ellison, David W.; Baker, Suzanne J.Journal of Clinical Oncology (2011), 29 (30), 3999-4006CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy no. abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas. Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21 % had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar. DIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.(b) Warren, K. E.; Killian, K.; Suuriniemi, M.; Wang, Y.; Quezado, M.; Meltzer, P. S. Genomic aberrations in pediatric diffuse intrinsic pontine gliomas Neuro-Oncology 2012, 14, 326– 332 DOI: 10.1093/neuonc/nor190
- 141Toogood, P. L.; Harvey, P. J.; Repine, J. T.; Sheehan, D. J.; VanderWel, S. N.; Zhou, H.; Keller, P. R.; McNamara, D. J.; Sherry, D.; Zhu, T.; Brodfuehrer, J.; Choi, C.; Barvian, M. R.; Fry, D. W. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6 J. Med. Chem. 2005, 48, 2388– 2406 DOI: 10.1021/jm049354h[ACS Full Text], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXitVGisL0%253D&md5=23cbe58426ff1975695712db7c1b128aDiscovery of a Potent and Selective Inhibitor of Cyclin-Dependent Kinase 4/6Toogood, Peter L.; Harvey, Patricia J.; Repine, Joseph T.; Sheehan, Derek J.; VanderWel, Scott N.; Zhou, Hairong; Keller, Paul R.; McNamara, Dennis J.; Sherry, Debra; Zhu, Tong; Brodfuehrer, Joanne; Choi, Chung; Barvian, Mark R.; Fry, David W.Journal of Medicinal Chemistry (2005), 48 (7), 2388-2406CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A pharmacol. approach to inhibition of cyclin-dependent kinases 4 and 6 (Cdk4/6) using highly selective small mol. inhibitors has the potential to provide novel cancer therapies for clin. use. Achieving high levels of selectivity for Cdk4/6, vs. other ATP-dependent kinases, presents a significant challenge. The pyrido[2,3-d]pyrimidin-7-one template provides an effective platform for the inhibition of a broad cross-section of kinases, including Cdks. It is now demonstrated that the modification of pyrido[2,3-d]pyrimidin-7-ones to include a 2-aminopyridine side chain at the C2-position provides inhibitors with exquisite selectivity for Cdk4/6 in vitro. This selectivity profile is recapitulated in cells where the most selective inhibitors create a G1 block at concns. up to 100-fold the IC50 for cell proliferation. On the basis of its selectivity profile and pharmacokinetic profile, compd. I (PD 0332991) was identified as a drug candidate for the treatment of cancer.
- 142Barton, K. L.; Misuraca, K.; Cordero, F.; Dobrikova, E.; Min, H. D.; Gromeier, M.; Kirsch, D. G.; Becher, O. J. PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma PLoS One 2013, 8, e77639 DOI: 10.1371/journal.pone.0077639
- 143Michaud, K.; Solomon, D. A.; Oermann, E.; Kim, J.-S.; Zhong, W.-Z.; Prados, M. D.; Ozawa, T.; James, C. D.; Waldman, T. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts Cancer Res. 2010, 70, 3228– 3238 DOI: 10.1158/0008-5472.CAN-09-4559
- 144Parrish, K. E.; Pokorny, J. L.; Mittapalli, R. K.; Bakken, K.; Sarkaria, J. N.; Elmquist, W. F. Efflux transporters at the blood-brain barrier limit delivery and efficacy of CDK4/6 inhibitor palbociclib (PD-0332991) in an orthotopic brain tumor model J. Pharmacol. Exp. Ther. 2015, 355, 264– 271 DOI: 10.1124/jpet.115.228213[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhslekuro%253D&md5=d40558cdcd30db24808eb55393607cbcEfflux transporters at the blood-brain barrier limit delivery and efficacy of cyclin-dependent kinase 4/6 inhibitor palbociclib (PD-0332991) in an orthotopic brain tumor modelParrish, Karen E.; Pokorny, Jenny; Mittapalli, Rajendar K.; Bakken, Katrina; Sarkaria, Jann N.; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2015), 355 (2), 264-271CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)6-Acetyl-8-cyclopentyl-5-methyl-2-([5-(piperazin-1-yl)pyridin-2- yl]amino)pyrido(2,3-d)pyrimidin-7(8H)-one [palbociclib (PD- 0332991)] is a cyclin-dependent kinase 4/6 inhibitor approved for the treatment of metastatic breast cancer and is currently undergoing clin. trials for many solid tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and has limited treatment options. The cyclin-dependent kinase 4/6 pathway is commonly dysregulated in GBM and is a promising target in treating this devastating disease. The blood-brain barrier (BBB) limits the delivery of drugs to invasive regions of GBM, where the efflux transporters P-glycoprotein and breast cancer resistance protein can prevent treatments from reaching the tumor. The purpose of this study was to examine the mechanisms limiting the effectiveness of palbociclib therapy in an orthotopic xenograft model. The in vitro intracellular accumulation results demonstrated that palbociclib is a substrate for both P-glycoprotein and breast cancer resistance protein. In vivo studies in transgenic mice confirmed that efflux transport is responsible for the limited brain distribution of palbociclib. There was an ∼115-fold increase in brain exposure at steady state in the transporter deficient mice when compared with wild-type mice, and the efflux inhibitor elacridar significantly increased palbociclib brain distribution. Efficacy studies demonstrated that palbociclib is an effective therapy when GBM22 tumor cells are implanted in the flank, but ineffective in an orthotopic (intracranial) model. Moreover, doses designed to mimic brain exposure were ineffective in treating flank tumors. These results demonstrate that efflux transport in the BBB is involved in limiting the brain distribution of palbociclib and this has crit. implications in detg. effective dosing regimens of palbociclib therapy in the treatment of brain tumors.
- 145Gelbert, L. M.; Cai, S.; Lin, X.; Sanchez-Martinez, C.; del Prado, M.; Lallena, M. J.; Torres, R.; Ajamie, R. T.; Wishart, G. N.; Flack, R. S.; Neubauer, B. L.; Young, J.; Chan, E. M.; Iversen, P.; Cronier, D.; Kreklau, E.; de Dios, A. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine Invest. New Drugs 2014, 32, 825– 837 DOI: 10.1007/s10637-014-0120-7[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVWrt7%252FN&md5=a90fee83bfe8da7e4a7474ccf02fc59aPreclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabineGelbert, Lawrence M.; Cai, Shufen; Lin, Xi; Sanchez-Martinez, Concepcion; del Prado, Miriam; Lallena, Maria Jose; Torres, Raquel; Ajamie, Rose T.; Wishart, Graham N.; Flack, Robert Steven; Neubauer, Blake Lee; Young, Jamie; Chan, Edward M.; Iversen, Philip; Cronier, Damien; Kreklau, Emiko; de Dios, AlfonsoInvestigational New Drugs (2014), 32 (5), 825-837CODEN: INNDDK; ISSN:0167-6997. (Springer)The G1 restriction point is crit. for regulating the cell cycle and is controlled by the Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This pathway is important because of its inactivation in a majority of human tumors. Transition through the restriction point requires phosphorylation of retinoblastoma protein (Rb) by CDK4/6, which are highly validated cancer drug targets. We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 h after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different histologies in tumor-bearing mice. LY2835219 is effective and well tolerated when administered up to 56 days in immunodeficient mice without significant loss of body wt. or tumor outgrowth. In calu-6 xenografts, LY2835219 in combination with gemcitabine enhanced in vivo antitumor activity without a G1 cell cycle arrest, but was assocd. with a redn. of ribonucleotide reductase expression. These results suggest LY2835219 may be used alone or in combination with std.-of-care cytotoxic therapy. In summary, we have identified a potent, orally active small-mol. inhibitor of CDK4/6 that is active in xenograft tumors. LY2835219 is currently in clin. development.
- 146Raub, T. J.; Wishart, G. N.; Kulanthaivel, P.; Staton, B. A.; Ajamie, R. T.; Sawada, G. A.; Gelbert, L. M.; Shannon, H. E.; Sanchez-Martinez, C.; De Dios, A. Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft Drug Metab. Dispos. 2015, 43, 1360– 1371 DOI: 10.1124/dmd.114.062745[Crossref], [PubMed], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlGrtbrL&md5=711886dd28d0e9ef3367183c8191ae1cBrain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograftRaub, Thomas J.; Wishart, Graham N.; Kulanthaivel, Palaniappan; Staton, Brian A.; Ajamie, Rose T.; Sawada, Geri A.; Gelbert, Lawrence M.; Shannon, Harlan E.; Sanchez-Martinez, Concepcion; De Dios, AlfonsoDrug Metabolism & Disposition (2015), 43 (9), 1360-1371CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. Targeting the CDK4/CDK6-cyclin D1-Rb-p16/ink4a pathway using a potent CDK4 and CDK6 kinase inhibitor has potential for treating primary central nervous system tumors such as glioblastoma and some peripheral tumors with high incidence of brain metastases. We compared central nervous system exposures of two orally bioavailable CDK4 and CDK6 inhibitors: abemaciclib, which is currently in advanced clin. development, and palbociclib (IBRANCE; Pfizer), which was recently approved by the U.S. Food and Drug Administration. Abemaciclib antitumor activity was assessed in s.c. and orthotopic glioma models alone and in combination with std. of care temozolomide (TMZ). Both inhibitors were substrates for xenobiotic efflux transporters P-glycoprotein and breast cancer resistant protein expressed at the blood-brain barrier. Brain Kp,uu values were less than 0.2 after an equimolar i.v. dose indicative of active efflux but were approx. 10-fold greater for abemaciclib than palbociclib. Kp,uu increased 2.8- and 21-fold, resp., when similarly dosed in P-gp-deficient mice. Abemaciclib had brain area under the curve (0-24 h) Kp,uu values of 0.03 in mice and 0.11 in rats after a 30 mg/kg p.o. dose. Orally dosed abemaciclib significantly increased survival in a rat orthotopic U87MG xenograft model compared with vehicle-treated animals, and efficacy coincided with a dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and CDK6 Ki values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats similar to TMZ, and the combination of abemaciclib and TMZ was additive or greater than additive. These data show that abemaciclib crosses the blood-brain barrier and confirm that both CDK4 and CDK6 inhibitors reach unbound brain levels in rodents that are expected to produce enzyme inhibition; however, abemaciclib brain levels are reached more efficiently at presumably lower doses than palbociclib and are potentially on target for a longer period of time.
- 147Sanchez-Martinez, C.; Gelbert, L. M.; Shannon, H.; De Dios, A.; Staton, B. A.; Ajamie, R. T.; Sawada, G.; Wishart, G. N.; Raub, T. J. Abstract B234: LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts Mol. Cancer Ther. 2011, 10, B234 DOI: 10.1158/1535-7163.TARG-11-B234
- 148https://clinicaltrials.gov/ct2/show/NCT02308020 (accessed June 12, 2016) .
- 149Asghar, U.; Witkiewicz, A. K.; Turner, N. C.; Knudsen, E. S. The history and future of targeting cyclin-dependent kinases in cancer therapy Nat. Rev. Drug Discovery 2015, 14, 130– 146 DOI: 10.1038/nrd4504[Crossref], [PubMed], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjvVCrtLc%253D&md5=113bcd2e99a8267119d180670d3c7761The history and future of targeting cyclin-dependent kinases in cancer therapyAsghar, Uzma; Witkiewicz, Agnieszka K.; Turner, Nicholas C.; Knudsen, Erik S.Nature Reviews Drug Discovery (2015), 14 (2), 130-146CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Cancer represents a pathol. manifestation of uncontrolled cell division; therefore, it has long been anticipated that our understanding of the basic principles of cell cycle control would result in effective cancer therapies. In particular, cyclin-dependent kinases (CDKs) that promote transition through the cell cycle were expected to be key therapeutic targets because many tumorigenic events ultimately drive proliferation by impinging on CDK4 or CDK6 complexes in the G1 phase of the cell cycle. Moreover, perturbations in chromosomal stability and aspects of S phase and G2/M control mediated by CDK2 and CDK1 are pivotal tumorigenic events. Translating this knowledge into successful clin. development of CDK inhibitors has historically been challenging, and numerous CDK inhibitors have demonstrated disappointing results in clin. trials. Here, we review the biol. of CDKs, the rationale for therapeutically targeting discrete kinase complexes and historical clin. results of CDK inhibitors. We also discuss how CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clin. activity.
- 150Cheng, C. K.; Gustafson, W. C.; Charron, E.; Houseman, B. T.; Zunder, E.; Goga, A.; Gray, N. S.; Pollok, B.; Oakes, S. A.; James, C. D.; Shokat, K. M.; Weiss, W. A.; Fan, Q. W. Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 12722– 12727 DOI: 10.1073/pnas.1202492109
- 151Senderowicz, A. M. Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials Invest. New Drugs 1999, 17, 313– 320 DOI: 10.1023/A:1006353008903
- 152Newcomb, E. W.; Tamasdan, C.; Entzminger, Y.; Arena, E.; Schnee, T.; Kim, M.; Crisan, D.; Lukyanov, Y.; Miller, D. C.; Zagzag, D. Flavopiridol inhibits the growth of GL261 gliomas in vivo Cell Cycle 2004, 3, 218– 222 DOI: 10.4161/cc.3.2.667
- 153Zhou, L.; Schmidt, K.; Nelson, F. R.; Zelesky, V.; Troutman, M. D.; Feng, B. The effect of breast cancer resistance protein and P-glycoprotein on the brain penetration of flavopiridol, imatinib mesylate (Gleevec), prazosin, and 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic acid (PF-407288) in mice Drug Metab. Dispos. 2009, 37, 946– 955 DOI: 10.1124/dmd.108.024489[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlsVWitLo%253D&md5=422881b70fa04474e0242a9c3a095093The effect of breast cancer resistance protein and P-glycoprotein on the brain penetration of flavopiridol, imatinib mesylate (Gleevec), prazosin, and 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic acid (PF-407288) in miceZhou, Lin; Schmidt, Kari; Nelson, Frederick R.; Zelesky, Veronica; Troutman, Matthew D.; Feng, BoDrug Metabolism and Disposition (2009), 37 (5), 946-955CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)The role of breast cancer resistance protein (Bcrp) and the combined activities of Bcrp and P-glycoprotein (P-gp, Mdr1a/1b) in limiting the brain penetration of drugs at the blood-brain barrier (BBB) were investigated using wild-type FVB, Mdr1a/1b(-/-), (-/-), Bcrp(-/-), and Mdr1a/1b(-/-), (-/-)Bcrp(-/-) mice. Four drugs, flavopiridol, imatinib mesylate (Gleevec), PF-407288, and prazosin, with different transport specificity for BCRP/Bcrp and MDR1/Mdr1a were selected, and the drug levels in plasma, cerebrospinal fluid, and brain of mice were detd. Flavopiridol and prazosin were identified as substrates for both mouse Bcrp and Mdr1a with greater transport assocd. with Bcrp. The brain/plasma (B/P) ratios at 0.5 and 2 h in Mdr1a/1b(-/-), (-/-) and Bcrp(-/-) mice were 1- to 2-fold for both compds., whereas the ratios in Mdr1a/1b(-/-), (-/-)Bcrp(-/-) mice were more than 5-fold of those obsd. in FVB mice. For imatinib, a better substrate of P-gp than Bcrp, the B/P ratios in Bcrp(-/-) were comparable to those in FVB mice, whereas the B/P ratios in Mdr1a/1b(-/-), (-/-) and Mdr1a/1b(-/-), (-/-)Bcrp(-/-) mice were more than 4- and 28-fold of those in FVB mice at both time points, resp. Finally, the Bcrp-specific substrate PF-407288 exhibited comparable B/P ratios in Mdr1a/1b(-/-), (-/-) and Bcrp(-/-) mice and slightly but significantly increased B/P ratios in Mdr1a/1b(-/-), (-/-)Bcrp(-/-) mice compared with those in FVB mice. The B/P ratios of compds. in Mdr1a/1b(-/-), (-/-)Bcrp(-/-) mice compared with those in Mdr1a/1b(-/-), (-/-) mice clearly demonstrate that Bcrp impairs the brain penetration of its substrates. Moreover, P-gp and Bcrp at BBB function synergistically to limit the brain penetration of shared substrates.
- 154Vita, M.; Abdel-Rehim, M.; Olofsson, S.; Hassan, Z.; Meurling, L.; Siden, A.; Siden, M.; Pettersson, T.; Hassan, M. Tissue distribution, pharmacokinetics and identification of roscovitine metabolites in rat Eur. J. Pharm. Sci. 2005, 25, 91– 103 DOI: 10.1016/j.ejps.2005.02.001[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjs1Kmsro%253D&md5=c4b7c6c0f7876cb67fb7ee6c91326262Tissue distribution, pharmacokinetics and identification of roscovitine metabolites in ratVita, Marina; Abdel-Rehim, Mohamed; Olofsson, Susanne; Hassan, Zuzana; Meurling, Lennart; Siden, Aake; Siden, Mabel; Pettersson, Tommy; Hassan, MoustaphaEuropean Journal of Pharmaceutical Sciences (2005), 25 (1), 91-103CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)The pharmacokinetics, biodistribution and the metabolic pathway of roscovitine were investigated in Sprague-Dawley rats after a single i.v. dose of 25 mg/kg. Blood, lungs, kidney, liver, testis, adipose tissue, spleen and brain were removed at different time-points. Plasma and tissue samples were analyzed using high performance liq. chromatog. The metabolites were identified using liq. chromatog./tandem mass spectrometry and NMR spectroscopy. Roscovitine (MW = 354) was cleared rapidly from circulation and highly distributed to the tissues. The elimination half-life of roscovitine in plasma and tissues was short (<30 min). A major metabolite (M1) was obsd. mainly in plasma and in lower levels in all other tissues. M1 was identified as conversion of the hydroxyl-group at C2 to carboxylic acid (MW = 368). A second metabolite (M2) was obsd. mainly in liver and kidney and identified as a hydroxylation product of the C8 of the purine-ring (MW = 370). A third metabolite (M3) was found in several organs and corresponded to N-dealkylation of the N9-iso-Pr side-chain (MW = 312). Roscovitine concns. in the brain were 30% of that obsd. in plasma, however no metabolites were detected in brain. In this investigation, three major metabolites of roscovitine were isolated and identified. Also, it was shown that roscovitine eliminates rapidly from both blood and tissues.
- 155Rajnai, Z.; Mehn, D.; Beery, E.; Okyar, A.; Jani, M.; Toth, G. K.; Fulop, F.; Levi, F.; Krajcsi, P. ATP-binding cassette B1 transports seliciclib (R-roscovitine), a cyclin-dependent kinase inhibitor Drug Metab. Dispos. 2010, 38, 2000– 2006 DOI: 10.1124/dmd.110.032805
- 156Paruch, K.; Dwyer, M. P.; Alvarez, C.; Brown, C.; Chan, T. Y.; Doll, R. J.; Keertikar, K.; Knutson, C.; McKittrick, B.; Rivera, J.; Rossman, R.; Tucker, G.; Fischmann, T.; Hruza, A.; Madison, V.; Nomeir, A. A.; Wang, Y.; Kirschmeier, P.; Lees, E.; Parry, D.; Sqambellone, N.; Seghezzi, W.; Schultz, L.; Shanahan, F.; Wiswell, D.; Xu, X.; Zhou, Q.; James, R. A.; Paradkar, V. M.; Park, H.; Rokosz, L. R.; Stauffer, T. M.; Guzi, T. J. Discovery of dinaciclib (SCH 727965): a potent and selective inhibitor of cyclin-dependent kinases ACS Med. Chem. Lett. 2010, 1, 204– 208 DOI: 10.1021/ml100051d[ACS Full Text], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmtFWis78%253D&md5=3b982547e064f658748fe4887a208659Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent KinasesParuch, Kamil; Dwyer, Michael P.; Alvarez, Carmen; Brown, Courtney; Chan, Tin-Yau; Doll, Ronald J.; Keertikar, Kerry; Knutson, Chad; McKittrick, Brian; Rivera, Jocelyn; Rossman, Randall; Tucker, Greg; Fischmann, Thierry; Hruza, Alan; Madison, Vincent; Nomeir, Amin A.; Wang, Yaolin; Kirschmeier, Paul; Lees, Emma; Parry, David; Sgambellone, Nicole; Seghezzi, Wolfgang; Schultz, Lesley; Shanahan, Frances; Wiswell, Derek; Xu, Xiaoying; Zhou, Quiao; James, Ray A.; Paradkar, Vidyadhar M.; Park, Haengsoon; Rokosz, Laura R.; Stauffer, Tara M.; Guzi, Timothy J.ACS Medicinal Chemistry Letters (2010), 1 (5), 204-208CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncol. therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clin. evaluation.
- 157Jane, E. P.; Premkumar, D. R.; Cavaleri, J. M.; Sutera, P. A.; Rajasekar, T.; Pollack, I. F. Dinaciclib, a cyclin-dependent kinase inhibitor promotes proteasomal degradation of Mcl-1 and enhances glioma cell lines J. Pharmacol. Exp. Ther. 2016, 356, 354– 365 DOI: 10.1124/jpet.115.230052[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpvVelsrc%253D&md5=0f25eb87db524546cb86ca6093150792Dinaciclib, a cyclin-dependent kinase inhibitor promotes proteasomal degradation of Mcl-1 and enhances ABT-737-mediated cell death in malignant human glioma cell linesJane, Esther P.; Premkumar, Daniel R.; Cavaleri, Jonathon M.; Sutera, Philip A.; Rajasekar, Thatchana; Pollack, Ian F.Journal of Pharmacology and Experimental Therapeutics (2016), 356 (2), 354-365CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)The prognosis for malignant glioma, the most common brain tumor, is still poor, underscoring the need to develop novel treatment strategies. Because glioma cells commonly exhibit genomic alterations involving genes that regulate cell-cycle control, there is a strong rationale for examg. the potential efficacy of strategies to counteract this process. In this study, we examd. the antiproliferative effects of the cyclin-dependent kinase inhibitor dinaciclib in malignant human glioma cell lines, with intact, deleted, or mutated p53 or phosphatase and tensin homolog on chromosome 10; intact or deleted or p14ARF or wild-type or amplified epidermal growth factor receptor. Dinaciclib inhibited cell proliferation and induced cell-cycle arrest at the G2/M checkpoint, independent of p53 mutational status. In a std. 72-h 3-[4,5-dimethylthiazol-2yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H, tetrazolium (MTS) assay, at clin. relevant concns., dose-dependent antiproliferative effects were obsd., but cell death was not induced. Moreover, the combination of conventional chemotherapeutic agents and various growth-signaling inhibitors with dinaciclib did not yield synergistic cytotoxicity. In contrast, combination of the Bcl-2/Bcl-xL inhibitors ABT-263 (4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide) or ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) with dinaciclib potentiated the apoptotic response induced by each single drug. The synergistic killing by ABT-737 with dinaciclib led to cell death accompanied by the hallmarks of apoptosis, including an early loss of the mitochondrial transmembrane potential; the release of cytochrome c, smac/DIABLO, and apoptosis-inducing factor; phosphatidylserine exposure on the plasma membrane surface and activation of caspases and poly ADP-ribose polymerase. Mechanistic studies revealed that dinaciclib promoted proteasomal degrdn. of Mcl-1. These observations may have important clin. implications for the design of exptl. treatment protocols for malignant human glioma.
- 158Loschmann, N.; Michaelis, M.; Rothweiler, F.; Zehner, R.; Cinati, J.; Voges, Y.; Sharifi, M.; Riecken, K.; Meyer, J.; von Deimling, A.; Fichter, I.; Ghafourian, T.; Westermann, F.; Cinatl, J. Testing of SNS-032 in a panel of human neuroblastoma cell lines with acquired resistance to a broad range of drugs Transl. Oncol. 2013, 6, 685– 696 DOI: 10.1593/tlo.13544[Crossref], [PubMed], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2czpt12ruw%253D%253D&md5=4ac4520700c6a093dfebba0b09cda08fTesting of SNS-032 in a Panel of Human Neuroblastoma Cell Lines with Acquired Resistance to a Broad Range of DrugsLoschmann Nadine; Rothweiler Florian; Cinatl Jaroslav; Voges Yvonne; Cinatl Jindrich Jr; Michaelis Martin; Zehner Richard; Sharifi Mohsen; Ghafourian Taravat; Riecken Kristoffer; Meyer Jochen; von Deimling Andreas; Fichtner Iduna; Westermann FrankTranslational oncology (2013), 6 (6), 685-96 ISSN:.Novel treatment options are needed for the successful therapy of patients with high-risk neuroblastoma. Here, we investigated the cyclin-dependent kinase (CDK) inhibitor SNS-032 in a panel of 109 neuroblastoma cell lines consisting of 19 parental cell lines and 90 sublines with acquired resistance to 14 different anticancer drugs. Seventy-three percent of the investigated neuroblastoma cell lines and all four investigated primary tumor samples displayed concentrations that reduce cell viability by 50% in the range of the therapeutic plasma levels reported for SNS-032 (<754 nM). Sixty-two percent of the cell lines and two of the primary samples displayed concentrations that reduce cell viability by 90% in this concentration range. SNS-032 also impaired the growth of the multidrug-resistant cisplatin-adapted UKF-NB-3 subline UKF-NB-3(r)CDDP(1000) in mice. ABCB1 expression (but not ABCG2 expression) conferred resistance to SNS-032. The antineuroblastoma effects of SNS-032 did not depend on functional p53. The antineuroblastoma mechanism of SNS-032 included CDK7 and CDK9 inhibition-mediated suppression of RNA synthesis and subsequent depletion of antiapoptotic proteins with a fast turnover rate including X-linked inhibitor of apoptosis (XIAP), myeloid cell leukemia sequence 1 (Mcl-1), baculoviral IAP repeat containing 2 (BIRC2; cIAP-1), and survivin. In conclusion, CDK7 and CDK9 represent promising drug targets and SNS-032 represents a potential treatment option for neuroblastoma including therapy-refractory cases.
- 159Kamath, A. V.; Chong, S.; Chang, M.; Marthe, P. H. P-glycoprotein plays a role in the oral absorption of BMS-387032, a potent cyclin-dependent kinase 2 inhibitor, in rats Cancer Chemother. Pharmacol. 2005, 55, 110– 116 DOI: 10.1007/s00280-004-0873-3[Crossref], [PubMed], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVGgtLzP&md5=728f59f80ef17fee59b85837e9d66885P-glycoprotein plays a role in the oral absorption of BMS-387032, a potent cyclin-dependent kinase 2 inhibitor, in ratsKamath, Amrita V.; Chong, Saeho; Chang, Ming; Marathe, Punit H.Cancer Chemotherapy and Pharmacology (2005), 55 (2), 110-116CODEN: CCPHDZ; ISSN:0344-5704. (Springer GmbH)Purpose: BMS-387032, a novel cyclin-dependent kinase 2 inhibitor, is currently in phase I clin. trials for anticancer therapy. The oral bioavailability of BMS-387032 has been found to be about 31 in rats. Absorption and first-pass metab. were evaluated as possible reasons for the incomplete oral bioavailability in rats. Methods: Male Sprague-Dawley rats were given single doses of BMS-387032 intraarterially (9.1 mg/kg), orally (9.1 mg/kg), or intraportally (10 mg/kg). The routes of excretion of BMS-387032 after i.v. dosing were investigated in bile-duct-cannulated rats. The rate of metab. of BMS-387032 was investigated in liver microsomes. The permeability of BMS-387032 was evaluated using Caco-2 cells, an in vitro model of the intestinal epithelium. To det. if BMS-387032 was a P-glycoprotein substrate, brain uptake studies were conducted in P-glycoprotein knockout vs. wildtype mice. Results: The exposure in rats after an intraportal dose was similar to that after an intraarterial dose, indicating that absorption may play a greater role than liver first-pass metab. in the low oral bioavailability seen in rats. After an i.v. dose, the percent of dose excreted unchanged in the urine and bile over a 9-h period was 28 and 11, resp. In vitro studies in rat liver microsomes showed low rates of metab. of BMS-387032. The Caco-2 cell permeability of BMS-387032 was <15 nm/s in the apical to basolateral direction, and 161 nm/s in the basolateral to apical direction, indicating that it may be a substrate for an intestinal efflux transporter. A P-glycoprotein binding assay showed that BMS-387032 might be a P-glycoprotein modulator. Brain penetration studies in mice showed brain levels of BMS-387032 about 3.5-fold higher in P-glycoprotein knockout mice than in wildtype mice, providing evidence of BMS-387032 being a P-glycoprotein substrate. Conclusions: Poor absorption may be playing a greater role than extensive first-pass metab. in the incomplete oral bioavailability of BMS-387032 seen in rats. The efflux transporter, P-glycoprotein, may be responsible for limiting absorption, as BMS-387032 appears to be a substrate of P-glycoprotein.
- 160Wyatt, P. G.; Woodhead, A. J.; Berdini, V.; Boulstridge, J. A.; Carr, M. G.; Cross, D. M.; Davis, D. J.; Devine, L. A.; Early, T. R.; Feltell, R. E.; Lewis, E. J.; McMenamin, R. L.; Navarro, E. F.; O’Brien, M. A.; O’Reilly, M.; Reule, M.; Saxty, G.; Seavers, L. C.; Smith, D. M.; Squires, M. S.; Trewartha, G.; Walker, M. T.; Woolford, A. J. Identification of N-(4-piperidinyl)-4-(2,6-dichlorbenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design J. Med. Chem. 2008, 51, 4986– 4999 DOI: 10.1021/jm800382h
- 161Cihalova, D.; Staud, F.; Ceckova, M. Interactions of cyclin-dependent kinase inhibitors AT-7519, flavopiridol and SNS-032 with ABCB1, ABCG2 and ABCC1 trasporters and their potential to overcome multidrug resistance in vitro Cancer Chemother. Pharmacol. 2015, 76, 105– 116 DOI: 10.1007/s00280-015-2772-1[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXos1Omsbc%253D&md5=3e8dcf19798145ffa656fc88dd2806d4Interactions of cyclin-dependent kinase inhibitors AT-7519, flavopiridol and SNS-032 with ABCB1, ABCG2 and ABCC1 transporters and their potential to overcome multidrug resistance in vitroCihalova, Daniela; Staud, Frantisek; Ceckova, MartinaCancer Chemotherapy and Pharmacology (2015), 76 (1), 105-116CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose: ATP-binding cassette (ABC) transporters play an important role in multidrug resistance (MDR) toward anticancer drugs. Here, we evaluated interactions of cyclin-dependent kinase inhibitors (CDKi) AT-7519, flavopiridol and SNS-032 with the following ABC transporters in vitro: P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-assocd. protein 1 (ABCC1). Methods: Inhibitory potency of studied CDKi to the transporters was evaluated by accumulation assays using fluorescent substrates and MDCKII cells overexpressing human ABCB1, ABCG2 or ABCC1. Resistance of transporter-expressing cells to the CDKi was evaluated by XTT proliferation assay. Obsd. interactions of CDKi were verified by ATPase assay in ABC transporter-expressing Sf9 membrane vesicles. Combination index anal. was addnl. performed in ABC transporter-expressing cancer cell lines, HepG2 and T47D. Results: Flavopiridol showed a significant inhibitory potency toward ABCG2 and ABCC1. SNS-032 also decreased ABCG2-mediated efflux, while AT-7519 failed to inhibit ABCB1, ABCG2 or ABCC1. Both flavopiridol and SNS-032 showed synergistic antiproliferative effects in combination with relevant ABC transporter substrates such as daunorubicin and topotecan in cancer cells. ABCB1 was found to confer significant resistance to AT-7519 and SNS-032, but not to flavopiridol. In contrast, ABCG2 and ABCC1 conferred resistance to flavopiridol, but not to AT-7519 and SNS-032. Conclusion: Our data provide detailed information on interactions of flavopiridol, SNS-032 and AT-7519 with ABC transporters, which may help elucidate the pharmacokinetic behavior and toxicity of these compds. Moreover, we show the ability of flavopiridol and SNS-032, but not AT-7519, to overcome ABC transporter-mediated MDR.
- 162Chu, X. J.; DePinto, W.; Bartkovitz, D.; So, S. S.; Vu, B. T.; Packman, K.; Lukacs, C.; Ding, Q.; Jiang, N.; Wang, K.; Goelzer, P.; Yin, X.; Smith, M. A.; Higgins, B. X.; Chen, Y.; Xiang, Q.; Moliterni, J.; Kaplan, G.; Graves, B.; Lovey, A.; Fotouhi, N. Discovery of [4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6-methoxyphenyl)methanone (R547), a potent and selective cyclin-dependent kinase inhibitor with significant in vivo antitumor activity J. Med. Chem. 2006, 49, 6549– 6560 DOI: 10.1021/jm0606138
- 163Byth, K. F.; Thomas, A.; Hughes, G.; Forder, C.; McGregor, A.; Geh, C.; Oakes, S.; Green, C.; Walker, M.; Newcombe, N.; Green, S.; Growcott, J.; Barker, A.; Wilkinson, R. W. AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts Mol. Cancer Ther. 2009, 8, 1856– 1866 DOI: 10.1158/1535-7163.MCT-08-0836[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosVyms70%253D&md5=2178bb1e046b382d71b846cce4644e35AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenograftsByth, Kate F.; Thomas, Andrew; Hughes, Gareth; Forder, Cheryl; McGregor, Alexandra; Geh, Catherine; Oakes, Sandra; Green, Clive; Walker, Mike; Newcombe, Nicholas; Green, Stephen; Growcott, Jim; Barker, Andy; Wilkinson, Robert W.Molecular Cancer Therapeutics (2009), 8 (7), 1856-1866CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Deregulation of the cell cycle has long been recognized as an essential driver of tumorigenesis, and agents that selectively target key cell cycle components continue to hold promise as potential therapeutics. We have developed AZD5438, a 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-methylsulfonylanilino) pyrimidine, as a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9 (IC50, 16, 6, and 20 nmol/L, resp.). In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC50 range, 0.2-1.7 μmol/L), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II C-terminal domain and blocking cell cycling at G2-M, S, and G1 phases. In vivo, when orally administered at either 50 mg/kg twice daily or 75 mg/kg once daily, AZD5438 inhibited human tumor xenograft growth (max. percentage tumor growth inhibition, range, 38-153; P < 0.05). In vivo, AZD5438 reduced the proportion of actively cycling cells. Further pharmacodynamic anal. of AZD5438-treated SW620 xenografts showed that efficacious doses of AZD5438 (>40% tumor growth inhibition) maintained suppression of biomarkers, such as phospho-pRbSer249/Thr252, for up to 16 h following a single oral dose. A comparison of different schedules indicated that chronic daily oral dosing provided optimal cover to ensure antitumor efficacy. These data indicate that broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has the pharmacol. profile that provides an ideal probe to test this premise. [Mol Cancer Ther 2009;8(7):1856-66].
- 164Zhang, I.; Zaorsky, N. G.; Palmer, J. D.; Mehra, R.; Lu, B. Targeting brain metastases in ALK-rearranged non-small-cell lung cancer Lancet Oncol. 2015, 16, e510– e521 DOI: 10.1016/S1470-2045(15)00013-3
- 165Cui, J. J.; Tran-Dube, M.; Shen, H.; Nambu, M.; Kung, P.; Pairish, M.; Jia, L.; Meng, J.; Funk, L.; Botrous, I.; McTigue, M.; Grodsky, N.; Ryan, K.; Padrique, E.; Alton, G.; Timofeevski, S.; Yamazaki, S.; Li, Q.; Zou, H.; Christensen, J.; Mroczkowski, B.; Bender, S.; Kania, R. S.; Edwards, M. P. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK) J. Med. Chem. 2011, 54, 6342– 6363 DOI: 10.1021/jm2007613[ACS Full Text], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVegtLrN&md5=dbab4c1b3e7c76180dbad04be2b6a474Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK)Cui, J. Jean; Tran-Dube, Michelle; Shen, Hong; Nambu, Mitchell; Kung, Pei-Pei; Pairish, Mason; Jia, Lei; Meng, Jerry; Funk, Lee; Botrous, Iriny; McTigue, Michele; Grodsky, Neil; Ryan, Kevin; Padrique, Ellen; Alton, Gordon; Timofeevski, Sergei; Yamazaki, Shinji; Li, Qiuhua; Zou, Helen; Christensen, James; Mroczkowski, Barbara; Bender, Steve; Kania, Robert S.; Edwards, Martin P.Journal of Medicinal Chemistry (2011), 54 (18), 6342-6363CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Because of the crit. roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncol. targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clin. candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.
- 166Camidge, D. R.; Bang, Y.-J.; Kwak, E. L.; Iafrate, A. J.; Varella-Garcia, M.; Fox, S. B.; Riely, G. J.; Solomon, B.; Ou, S.-H. I.; Kim, D.-W.; Salgia, R.; Fidias, P.; Engelman, J. A.; Gandhi, L.; Janne, P. A.; Costa, D. B.; Shapiro, G. I.; LoRusso, P.; Ruffner, K.; Stephenson, P.; Tang, Y.; Wilner, K.; Clark, J. W.; Shaw, A. T. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study Lancet Oncol. 2012, 13, 1011– 1019 DOI: 10.1016/S1470-2045(12)70344-3[Crossref], [PubMed], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVCjsb3E&md5=bd3aec44b197ee2f4c9d49ea540a672fActivity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 studyCamidge, D. Ross; Bang, Yung-Jue; Kwak, Eunice L.; Iafrate, A. John; Varella-Garcia, Marileila; Fox, Stephen B.; Riely, Gregory J.; Solomon, Benjamin; Ou, Sai-Hong I.; Kim, Dong-Wan; Salgia, Ravi; Fidias, Panagiotis; Engelman, Jeffrey A.; Gandhi, Leena; Jaenne, Pasi A.; Costa, Daniel B.; Shapiro, Geoffrey I.; LoRusso, Patricia; Ruffner, Katherine; Stephenson, Patricia; Tang, Yiyun; Wilner, Keith; Clark, Jeffrey W.; Shaw, Alice T.Lancet Oncology (2012), 13 (10), 1011-1019CODEN: LOANBN; ISSN:1470-2045. (Elsevier Ltd.)Summary: Background: ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. Methods: In this phase 1 study, patients with ALK-pos. stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumor responses, duration of response, time to tumor response, progression-free survival (PFS), overall survival at 6 and 12 mo, and detn. of the safety and tolerability and characterization of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analyzed in evaluable patients and PFS and safety were analyzed in all patients. This study is registered with ClinicalTrials.gov, no. NCT00585195. Findings: Between Aug 27, 2008, and June 1, 2011, 149 ALK-pos. patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3-68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 wk (range 2·1-39·6) and median duration of response was 49·1 wk (95% CI 39·3-75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 mo (95% CI 7·7-12·8). Median overall survival data are not yet mature, but estd. overall survival at 6 and 12 mo was 87·9% (95% CI 81·3-92·3) and 74·8% (66·4-81·5), resp. 39 patients continued to receive crizotinib for more than 2 wk after progression because of perceived ongoing clin. benefit from the drug (12 for at least 6 mo from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral edema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphatemia (n=6), and lymphopenia (n=6). Interpretation: Crizotinib is well tolerated with rapid, durable responses in patients with ALK-pos. NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed. Funding: Pfizer.
- 167Otterson, G. A.; Riely, G. J.; Shaw, A. T.; Crino, L.; Kim, D.-W.; Marins, R.; Salgia, R.; Zhou, C.; Solomon, B. J.; Wilner, K. D.; Polli, A.; Tang, Y.; Bartlett, C. H.; Ou, S.-H. I. Clinical characteristics of ALK+ NSCLC patients treated with crizotnib beyond disease progression: potential implications for management J. Clin. Oncol. 2012, 30 (Suppl.) 7600
- 168Costa, D. B.; Kobayashi, S.; Pandya, S. S.; Yeo, W.-L.; Shen, Z.; Tan, W.; Wilner, K. D. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib J. Clin. Oncol. 2011, 29, e443– 445 DOI: 10.1200/JCO.2010.34.1313
- 169Johnson, T. W.; Richardson, P. F.; Bailey, S.; Brooun, A.; Burke, B. J.; Collins, M. R.; Cui, J. J.; Deal, J. G.; Deng, Y.-L.; Dinh, D.; Engstrom, L. D.; He, M.; Hoffman, J.; Hoffman, R. L.; Huang, Q.; Kania, R. S.; Kath, J. C.; Lam, H.; Lam, J. L.; Le, P. T.; Lingardo, L.; Liu, W.; McTigue, M.; Palmer, C. L.; Sach, N. W.; Smeal, T.; Smith, G. L.; Stewart, A. E.; Timofeevski, S.; Zhu, H.; Zhu, J.; Zou, H. Y.; Edwards, M. P. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations J. Med. Chem. 2014, 57, 4720– 4744 DOI: 10.1021/jm500261q
- 170Awad, M. M.; Shaw, A. T. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond Clin. Adv. Hematol. Oncol. 2014, 12, 429– 439[PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M3htl2qug%253D%253D&md5=ae4655774258c9265a283749559ac393ALK inhibitors in non-small cell lung cancer: crizotinib and beyondAwad Mark M; Shaw Alice TClinical advances in hematology & oncology : H&O (2014), 12 (7), 429-39 ISSN:1543-0790.The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years, a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC, including ceritinib (LDK378), alectinib (RO5424802/CH5424802), AP26113, ASP3026, TSR-011, PF-06463922, RXDX-101, X-396, and CEP-37440. Cancers harboring ALK rearrangements may also be susceptible to treatment with heat shock protein 90 inhibitors. This review focuses on the pharmacologic and clinical properties of these compounds, either as monotherapies or in combination with other drugs. With so many ALK inhibitors in development, the challenges of how these agents should be studied and ultimately prescribed are also discussed.
- 171Marsilje, T. H.; Pei, W.; Chen, B.; Lu, W.; Uno, T.; Jin, Y.; Jiang, T.; Kim, S.; Li, N.; Warmuth, M.; Sarkisova, Y.; Sun, F.; Steffy, A.; Pferdekamper, A. C.; Li, A. G.; Joseph, S. B.; Kim, Y.; Liu, B.; Tuntland, T.; Cui, X.; Gray, N. S.; Steensma, R.; Wan, Y.; Jiang, J.; Chopiuk, G.; Li, J.; Gordon, W. P.; Richmond, W.; Johnson, K.; Chang, J.; Groessl, T.; He, Y.-Q.; Phimister, A.; Aycinena, A.; Lee, C. C.; Bursulaya, B.; Karanewsky, D. S.; Seidel, H. M.; Harris, J. L.; Michellys, P.-Y. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials J. Med. Chem. 2013, 56, 5675– 5690 DOI: 10.1021/jm400402q[ACS Full Text], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptVWjs7g%253D&md5=4b8f66e4acb27efe814956d7d0016068Synthesis, Structure-Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical TrialsMarsilje, Thomas H.; Pei, Wei; Chen, Bei; Lu, Wenshuo; Uno, Tetsuo; Jin, Yunho; Jiang, Tao; Kim, Sungjoon; Li, Nanxin; Warmuth, Markus; Sarkisova, Yelena; Sun, Frank; Steffy, Auzon; Pferdekamper, AnneMarie C.; Li, Allen G.; Joseph, Sean B.; Kim, Young; Liu, Bo; Tuntland, Tove; Cui, Xiaoming; Gray, Nathanael S.; Steensma, Ruo; Wan, Yongqin; Jiang, Jiqing; Chopiuk, Greg; Li, Jie; Gordon, W. Perry; Richmond, Wendy; Johnson, Kevin; Chang, Jonathan; Groessl, Todd; He, You-Qun; Phimister, Andrew; Aycinena, Alex; Lee, Christian C.; Bursulaya, Badry; Karanewsky, Donald S.; Seidel, H. Martin; Harris, Jennifer L.; Michellys, Pierre-YvesJournal of Medicinal Chemistry (2013), 56 (14), 5675-5690CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis, preclin. profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor (I; LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor (II; TAE684). Compd. I is currently in phase 1 and phase 2 clin. trials with substantial antitumor activity being obsd. in ALK-pos. cancer patients.
- 172(a) Shaw, A. T.; Kim, D. W.; Mehra, R.; Tan, D. S. W.; Felip, E.; Chow, L. Q. M.; Camidge, D. R.; Vansteenkiste, J.; Sharma, S.; De Pas, T.; Riely, G. J.; Solomon, B. J.; Wolf, J.; Thomas, M.; Schuler, M.; Liu, G.; Santoro, A.; Lau, Y. Y.; Goldwasser, M.; Boral, A. L.; Engelman, J. A. Ceritinib in ALK-rearranged non-small-cell lung cancer N. Engl. J. Med. 2014, 370, 1189– 1197 DOI: 10.1056/NEJMoa1311107[Crossref], [PubMed], [CAS], Google Scholar172ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlvVCitL0%253D&md5=dff3054469948ceb26a00e3eccac56c1Ceritinib in ALK-rearranged non-small-cell lung cancerShaw, Alice T.; Kim, Dong-Wan; Mehra, Ranee; Tan, Daniel S. W.; Felip, Enriqueta; Chow, Laura Q. M.; Camidge, Ross; Vansteenkiste, Johan; Sharma, Sunil; De Pas, Tommaso; Riely, Gregory J.; Solomon, Benjamin J.; Wolf, Juergen; Thomas, Michael; Schuler, Martin; Liu, Geoffrey; Santoro, Armando; Lau, Yvonne Y.; Goldwasser, Meredith; Boral, Anthony L.; Engelman, Jeffrey A.New England Journal of Medicine (2014), 370 (13), 1189-1197CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)Background: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclin. studies. Methods: In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the max. tolerated dose. Patients were assessed to det. the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. Results: A total of 59 patients were enrolled in the dose-escalation phase. The max. tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an addnl. 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were obsd. in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 mo (95% CI, 5.6 to 9.5). Conclusions: Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK.(b) Kim, D.-W.; Mehra, R.; Tan, D. S.-W.; Felip, E.; Chow, L. Q. M.; Camidge, D. R.; Vansteenkiste, J. F.; Sharma, S.; De Pas, T.; Riely, G. J.; Solomon, B. J.; Wolf, J.; Thomas, M.; Schuler, M. H.; Liu, G.; Santoro, A.; Geraldes, M.; Boral, A.; Yovine, A. J.; Shaw, A. T. Ceritinib in advanced anaplastic lymphoma (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): results of the ASCEND-1 trial J. Clin. Oncol. 2014, 32 (Suppl.) 8003(c) Shaw, A.; Mehra, R.; Tan, D. S. W.; Felip, E.; Chow, L. Q.; Camidge, D. R.; Vansteenkiste, J. R.; Sharma, S.; De Pas, T.; Riely, G. J.; Solomon, B.; Wolf, J.; Thomas, M.; Schuler, M.; Liu, G.; Santoro, A.; Geraldes, M.; Boral, A. L.; Yovine, A.; Kim, D. Evaluation of ceritinib-treated patients (pts) with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) and brain metastases in the ASCEND-1 Study Ann. Oncol. 2014, 25 (Suppl. 4) iv455– iv456
- 173Kinoshita, K.; Asoh, K.; Furuichi, N.; Ito, T.; Kawada, H.; Hara, S.; Ohwada, J.; Miyagi, T.; Kobayashi, T.; Takanashi, K.; Tsukaguchi, T.; Sakamoto, H.; Tsukuda, T.; Oikawa, N. Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802) Bioorg. Med. Chem. 2012, 20, 1271– 1280 DOI: 10.1016/j.bmc.2011.12.021[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFSmu70%253D&md5=cff263d2dd8c66de9fd687530fdadb06Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802)Kinoshita, Kazutomo; Asoh, Kohsuke; Furuichi, Noriyuki; Ito, Toshiya; Kawada, Hatsuo; Hara, Sousuke; Ohwada, Jun; Miyagi, Takuho; Kobayashi, Takamitsu; Takanashi, Kenji; Tsukaguchi, Toshiyuki; Sakamoto, Hiroshi; Tsukuda, Takuo; Oikawa, NobuhiroBioorganic & Medicinal Chemistry (2012), 20 (3), 1271-1280CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, esp. non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clin. candidate.
- 174Kodama, T.; Hasegawa, M.; Takanashi, K.; Sakurai, Y.; Kondoh, O.; Sakamoto, H. Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases Cancer Chemother. Pharmacol. 2014, 74, 1023– 1028 DOI: 10.1007/s00280-014-2578-6[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFeju7%252FK&md5=19b3fa282fb58bf492714d39207edac6Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastasesKodama, Tatsushi; Hasegawa, Masami; Takanashi, Kenji; Sakurai, Yuji; Kondoh, Osamu; Sakamoto, HiroshiCancer Chemotherapy and Pharmacology (2014), 74 (5), 1023-1028CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose: The clin. efficacy of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been demonstrated in ALK fusion-pos. non-small cell lung cancer (NSCLC); however, brain metastases are frequent sites of initial failure in patients due to poor penetration of the central nervous system by crizotinib. Here, we examd. the efficacy of a selective ALK inhibitor alectinib/CH5424802 in preclin. models of intracranial tumors. Methods: We established intracranial tumor implantation mouse models of EML4-ALK-pos. NSCLC NCI-H2228 and examd. the antitumor activity of alectinib in this model. Plasma distribution and brain distribution of alectinib were examd. by quant. whole-body autoradiog. administrating a single oral dose of 14C-labeled alectinib to rats. The drug permeability of alectinib was evaluated in Caco-2 cell. Results: Alectinib resulted in regression of NCI-H2228 tumor in mouse brain and provided a survival benefit. In a pharmacokinetic study using rats, alectinib showed a high brain-to-plasma ratio, and in an in vitro drug permeability study using Caco-2 cells, alectinib was not transported by P-glycoprotein efflux transporter that is a key factor in blood-brain barrier penetration. Conclusions: We established intracranial tumor implantation models of EML4-ALK-pos. NSCLC. Alectinib showed potent efficacy against intracranial EML4-ALK-pos. tumor. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with brain metastases.
- 175(a) Gadgeel, S. M.; Gandhi, L.; Riely, G. J.; Chiappori, A. A.; West, H. L.; Azada, M. C.; Morcos, P. N.; Lee, R.-M.; Garcia, L.; Yu, L.; Boisserie, F.; Di Laurenzio, L.; Golding, S.; Sato, J.; Yokoyama, S.; Tanaka, T.; Ou, S.-H. I. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study Lancet Oncol. 2014, 15, 1119– 1128 DOI: 10.1016/S1470-2045(14)70362-6[Crossref], [PubMed], [CAS], Google Scholar175ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVSmt77K&md5=aa56d295472ea5dcb29070a4e39d420aSafety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 studyGadgeel, Shirish M.; Gandhi, Leena; Riely, Gregory J.; Chiappori, Alberto A.; West, Howard L.; Azada, Michele C.; Morcos, Peter N.; Lee, Ruey-Min; Garcia, Linta; Yu, Li; Boisserie, Frederic; Di Laurenzio, Laura; Golding, Sophie; Sato, Jotaro; Yokoyama, Shumpei; Tanaka, Tomohiro; Ou, Sai-Hong IgnatiusLancet Oncology (2014), 15 (10), 1119-1128CODEN: LOANBN; ISSN:1470-2045. (Elsevier Ltd.)Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progression-free survival of 8-11 mo while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clin. activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib. We enrolled patients with ALK-rearranged NSCLC who progressed on or were intolerant to crizotinib. We administered various oral doses of alectinib (300-900 mg twice a day) during the dose-escalation portion of the study (phase 1), to ascertain the recommended dose for phase 2. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.1) to investigate the activity of alectinib in all patients with a baseline scan and at least one post-treatment scan (CT or MRI), with central radiol. review of individuals with brain metastases. We assessed safety in all patients who received at least one dose of alectinib. Here, we present data for the phase 1 portion of the study, the primary objective of which was to establish the recommended phase 2 dose; phase 2 is ongoing. This trial is registered at ClinicalTrials.gov, no. NCT01588028.47 patients were enrolled. Alectinib was well tolerated, with the most common adverse events being fatigue (14 [30%]; all grade 1-2), myalgia (eight [17%]; all grade 1-2), and peripheral edema (seven [15%] grade 1-2, one [2%] grade 3). Dose-limiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day; one individual had grade 3 headache and the other had grade 3 neutropenia. The most common grade 3-4 adverse events were increased levels of γ-glutamyl transpeptidase (two [4%]), a redn. in the no. of neutrophils (two [4%]), and hypophosphatemia (two [4%]). Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib: acute renal failure; pleural effusion and pericardial effusion; and brain metastasis. At data cut-off (median follow-up 126 days [IQR 84-217]), 44 patients could be assessed for activity. Investigator-assessed objective responses were noted in 24 (55%) patients, with a confirmed complete response in one (2%), a confirmed partial response in 14 (32%), and an unconfirmed partial response in nine (20%). 16 (36%) patients had stable disease; the remaining four (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had an objective response; six (29%) had a complete response (three unconfirmed) and five (24%) had a partial response (one unconfirmed); eight (38%) patients had stable disease and the remaining two (10%) had progressive disease. Pharmacokinetic data indicated that mean exposure (AUC0-10) after multiple doses of alectinib (300-600 mg twice a day) was dose-dependent. Alectinib was well tolerated, with promising antitumor activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2. Chugai Pharmaceuticals, F Hoffmann La-Roche.(b) Ajimizu, H.; Kim, Y. H.; Mishima, M. Rapid response of brain metastases to alectinib in a patient with non-small-cell lung cancer resistant to crizotinib Med. Oncol. 2015, 32, 3 DOI: 10.1007/s12032-014-0477-7(c) Gainor, J. F.; Sherman, C. A.; Willoughby, K.; Logan, J.; Kennedy, E.; Brastianos, P. K.; Chi, A. S.; Shaw, A. T. Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib J. Thorac. Oncol. 2015, 10, 232– 236 DOI: 10.1097/JTO.0000000000000455[Crossref], [PubMed], [CAS], Google Scholar175chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVentLY%253D&md5=02a74597e914c4472f8d4d7edc128ba1Alectinib Salvages CNS Relapses in ALK-Positive Lung Cancer Patients Previously Treated with Crizotinib and CeritinibGainor, Justin F.; Sherman, Carol A.; Willoughby, Kathryn; Logan, Jennifer; Kennedy, Elizabeth; Brastianos, Priscilla K.; Chi, Andrew S.; Shaw, Alice T.Journal of Thoracic Oncology (2015), 10 (2), 232-236CODEN: JTOOB7; ISSN:1556-0864. (Lippincott Williams & Wilkins)Background: Leptomeningeal metastases (LM) are an increasingly frequent and devastating complication of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). Currently, the optimal management of LM in ALK-pos. patients remains poorly understood as these patients have been routinely excluded from clin. trials. Methods: We describe four ALK-pos. patients with LM who were treated with the next-generation ALK inhibitor alectinib through single-patient, compassionate use protocols at two institutions. All patients had previously been treated with both FDA-approved ALK inhibitors-crizotinib and ceritinib. Patients received alectinib at a starting dose of 600 mg twice daily. Results: Four ALK-pos. NSCLC patients with symptomatic leptomeningeal disease were identified. Three of four patients experienced significant clin. and radiog. improvements in LM upon treatment with alectinib. A fourth patient had stable intracranial disease for 4 mo before eventual systemic disease progression. Overall, alectinib was well tolerated. One patient required dose redn. due to grade 2 hyperbilirubinemia. Conclusions: Alectinib is active in ALK-rearranged NSCLC patients with LM, including in patients previously treated with crizotinib and ceritinib. Addnl. prospective studies of alectinib in ALK-pos. patients with LM are warranted.
- 176Menichincheri, M.; Ardini, E.; Magnaghi, P.; Avanzi, N.; Banfi, P.; Bossi, R.; Buffa, L.; Canevari, G.; Ceriani, L.; Colombo, M.; Corti, L.; Donati, D.; Fasolini, M.; Felder, E.; Fiorelli, C.; Fiorentini, F.; Galvani, A.; Isacchi, A.; Borgia, A. L.; Marchionni, C.; Nesi, M.; Orrenius, C.; Panzeri, A.; Pesenti, E.; Rusconi, L.; Saccardo, M. B.; Vanotti, E.; Perrone, E.; Orsini, P. Discovery of entrectinib: a new 3-aminoindazole as a potent anaplastic lymphoma kinase (ALK), c-ros oncogene 1 kinase (ROS1), and pan-tropomyosin receptor kinases (pan-TRKs) inhibitor J. Med. Chem. 2016, 59, 3392– 3408 DOI: 10.1021/acs.jmedchem.6b00064[ACS Full Text], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xks1eitL8%253D&md5=140217fba2ac81d71600f7344f2d8a3eDiscovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitorMenichincheri, Maria; Ardini, Elena; Magnaghi, Paola; Avanzi, Nilla; Banfi, Patrizia; Bossi, Roberto; Buffa, Laura; Canevari, Giulia; Ceriani, Lucio; Colombo, Maristella; Corti, Luca; Donati, Daniele; Fasolini, Marina; Felder, Eduard; Fiorelli, Claudio; Fiorentini, Francesco; Galvani, Arturo; Isacchi, Antonella; Borgia, Andrea Lombardi; Marchionni, Chiara; Nesi, Marcella; Orrenius, Christian; Panzeri, Achille; Pesenti, Enrico; Rusconi, Luisa; Saccardo, Maria Beatrice; Vanotti, Ermes; Perrone, Ettore; Orsini, PaoloJournal of Medicinal Chemistry (2016), 59 (7), 3392-3408CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clin. activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within the ALK drug discovery program, the authors identified compd. I, a novel 3-aminoindazole active on ALK in biochem. and in cellular assays. Its optimization led to compd. II (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clin. trial for the treatment of patients affected by ALK-, ROS1-, and TRK-pos. tumors.
- 177Farago, A. F.; Le, L. P.; Zheng, Z.; Muzikansky, A.; Drilon, A.; Patel, M.; Bauer, T. M.; Liu, S. V.; Ou, S. I.; Jackman, D.; Costa, D. B.; Multani, P. S.; Li, G. G.; Hornby, Z.; Chow-Maneval, E.; Luo, D.; Lim, J. E.; Iafrate, A. J.; Shaw, A. T. Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer J. Thorac. Oncol. 2015, 10, 1670– 1674 DOI: 10.1097/01.JTO.0000473485.38553.f0[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvF2it7rN&md5=1d0160c35a3bdbdcb2ebd01313cc18baDurable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung CancerFarago, Anna F.; Le, Long P.; Zheng, Zongli; Muzikansky, Alona; Drilon, Alexander; Patel, Manish; Bauer, Todd M.; Liu, Stephen V.; Ou, Sai-Hong I.; Jackman, David; Costa, Daniel B.; Multani, Pratik S.; Li, Gary G.; Hornby, Zachary; Chow-Maneval, Edna; Luo, David; Lim, Jonathan E.; Iafrate, Anthony J.; Shaw, Alice T.Journal of Thoracic Oncology (2015), 10 (12), 1670-1674CODEN: JTOOB7; ISSN:1556-0864. (Lippincott Williams & Wilkins)Introduction: Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to det. the frequency of NTRK1 rearrangements in NSCLC and to assess the clin. activity of entrectinib. Methods: We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment. Results: We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3-4 adverse events. Within three weeks of starting on treatment, the patient reported resoln. of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resoln. of all brain metastases. This patient has continued on treatment for over 6 mo with an ongoing PR. Conclusions: Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.
- 178Mori, M.; Ueno, Y.; Konagai, S.; Fushiki, H.; Shimada, I.; Kondoh, Y.; Saito, R.; Mori, K.; Shindou, N.; Soga, T.; Sakagami, H.; Furutani, T.; Doihara, H.; Kudoh, M.; Kuromitsu, S. The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs survival in non-small cell lung cancer model mice Mol. Cancer Ther. 2014, 13, 329– 340 DOI: 10.1158/1535-7163.MCT-13-0395[Crossref], [PubMed], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFWmsb8%253D&md5=4d8de3814f3f8fa198f2d3acb5d3860aThe Selective Anaplastic Lymphoma Receptor Tyrosine Kinase Inhibitor ASP3026 Induces Tumor Regression and Prolongs Survival in Non-Small Cell Lung Cancer Model MiceMori, Masamichi; Ueno, Yoko; Konagai, Satoshi; Fushiki, Hiroshi; Shimada, Itsuro; Kondoh, Yutaka; Saito, Rika; Mori, Kenichi; Shindou, Nobuaki; Soga, Takatoshi; Sakagami, Hideki; Furutani, Takashi; Doihara, Hitoshi; Kudoh, Masafumi; Kuromitsu, SadaoMolecular Cancer Therapeutics (2014), 13 (2), 329-340CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Activation of anaplastic lymphoma receptor tyrosine kinase (ALK) is involved in the pathogenesis of several carcinomas, including non-small cell lung cancer (NSCLC). Echinoderm microtubule-assocd. protein like 4 (EML4)-ALK, which is derived from the rearrangement of ALK and EML4 genes, has been validated as a therapeutic target in a subset of patients with NSCLC. Here, we investigated the effects of ASP3026, a novel small-mol. ALK inhibitor, against ALK-driven NSCLC. ASP3026 inhibited ALK activity in an ATP-competitive manner and had an inhibitory spectrum that differed from that of crizotinib, a dual ALK/MET inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, orally administered ASP3026 was well absorbed in tumor tissues, reaching concns. >10-fold higher than those in plasma, and induced tumor regression with a wide therapeutic margin between efficacious and toxic doses. In the same mouse model, ASP3026 enhanced the antitumor activities of paclitaxel and pemetrexed without affecting body wt. ASP3026 also showed potent antitumor activities, including tumor shrinkage to a nondetectable level, in hEML4-ALK transgenic mice and prolonged survival in mice with intrapleural NCI-H2228 xenografts. In an intrahepatic xenograft model using NCI-H2228 cells, ASP3026 induced continuous tumor regression, whereas mice treated with crizotinib showed tumor relapse after an initial response. Finally, ASP3026 exhibited potent antitumor activity against cells expressing EML4-ALK with a mutation in the gatekeeper position (L1196M) that confers crizotinib resistance. Taken together, these findings indicate that ASP3026 has potential efficacy for NSCLC and is expected to improve the therapeutic outcomes of patients with cancer with ALK abnormality. Mol Cancer Ther; 13(2); 329-40. ©2014 AACR.
- 179Fushiki, H.; Saito, R.; Jitsuoka, M.; Shimada, I.; Kondoh, Y.; Sakagami, H.; Funatsu, Y.; Noda, A.; Murakami, Y.; Miyoshi, S.; Ueon, Y.; Konagai, S.; Soga, T.; Nishimura, S.; Mori, M.; Kuromitsu, S. Abstract 2678: First demonstration of in vivo PET imaging for ALK inhibitor using [11C]ASP3026, a novel brain-permeable type of ALK inhibitor Cancer Res. 2013, 73 (Suppl.) 2678 DOI: 10.1158/1538-7445.AM2013-2678
- 180Huang, W. S.; Liu, S.; Zou, D.; Thomas, M.; Wang, Y.; Zhou, T.; Romero, J.; Kohlmann, A.; Li, F.; Qi, J.; Cai, L.; Dwight, T. A.; Xu, Y.; Xu, R.; Dodd, R.; Toms, A.; Parillon, L.; Lu, X.; Anjum, R.; Zhang, S.; Wang, F.; Keats, J.; Wardwell, S. D.; Ning, Y.; Xu, Q.; Moran, L. E.; Mohemmad, Q. K.; Jang, H. G.; Clackson, T.; Narashimhan, N. I.; Rivera, V. M.; Zhu, X.; Dalgarno, D.; Shakespeare, W. C. Discovery of brigatinib (AP26113), a phosphine oxide-containing, potent, orally active inhibitor of analplastic lymphoma kinase J. Med. Chem. 2016, 59, 4948– 4964 DOI: 10.1021/acs.jmedchem.6b00306
- 181Gettinger, S. N.; Bazhenova, L.; Salgia, R.; Langer, C. J.; Gold, K. A.; Rosell, R.; Shaw, A. T.; Weiss, G. J.; Narasimhan, N. I.; Dorer, D. J.; Rivera, V. M.; Clackson, T.; Haluska, F. G.; Camidge, D. R. Updated efficacy and safety of the ALK inhibitor AP26113 in patients with advanced malignancies, including ALK+ non-small cell lung cancer J. Thorac. Oncol. 2013, 8 (Suppl. 2) S296
- 182Camidge, D. R.; Bazhenova, L.; Salgia, R.; Langer, C. J.; Gold, K. A.; Rosell, R.; Shaw, A. T.; Weiss, G. J.; Narasimhan, N. I.; Dorer, D. J.; Rivera, V. M.; Clackson, T. P.; Conlan, M. G.; Kerstein, D.; Haluska, F. G.; Gettinger, S. N. Safety and efficacy of brigatinib (AP26113) in advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC) J. Clin. Oncol. 2015, 33 (Suppl.) 8062
- 183Lovly, C. M.; Heuckmann, J. M.; de Stanchina, E.; Chen, H.; Thomas, R. K.; Liang, C.; Pao, W. Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors Cancer Res. 2011, 71, 4920– 4931 DOI: 10.1158/0008-5472.CAN-10-3879[Crossref], [PubMed], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXovFartro%253D&md5=000cbd1295c9d9fa6a43027f08c31247Insights into ALK-Driven Cancers Revealed through Development of Novel ALK Tyrosine Kinase InhibitorsLovly, Christine M.; Heuckmann, Johannes M.; de Stanchina, Elisa; Chen, Heidi; Thomas, Roman K.; Liang, Chris; Pao, WilliamCancer Research (2011), 71 (14), 4920-4931CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers, where ALK represents a rational therapeutic target in these settings. In this study, we report the identification and biol. characterization of X-376 and X-396, two potent and highly specific ALK small mol. tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays, X-376 and X-396 were more potent inhibitors of ALK but less potent inhibitors of MET compared to PF-02341066 (PF-1066), an ALK/MET dual TKI currently in clin. trials. Both X-376 and X-396 displayed potent antitumor activity in vivo with favorable pharmacokinetic and toxicity profiles. Similar levels of drug sensitivity were displayed by the three most common ALK fusion proteins in lung cancer (EML4-ALK variants E13;A20, E20;A20, and E6b;A20) as well as a KIF5B-ALK fusion protein. Moreover, X-396 could potently inhibit ALK kinases engineered with two point mutations assocd. with acquired resistance to PF-1066, L1196M, and C1156Y, when engineered into an E13;A20 fusion variant. Finally, X-396 displayed synergistic growth inhibitory activity when combined with the mTOR inhibitor rapamycin. Our findings offer preclin. proof-of-concept for use of these novel agents to improve therapeutic outcomes of patients with mutant ALK-driven malignancies. Cancer Res; 71(14); 4920-31.
- 184Lin, N. U.; Dieras, V.; Paul, D.; Lossignol, D.; Christodoulou, C.; Stemmler, H.-J.; Roche, H.; Liu, M. C.; Greil, R.; Ciruelos, E.; Loibl, S.; Gori, S.; Wardley, A.; Yardley, D.; Brufsky, A.; Blum, J. L.; Rubin, S. D.; Dharan, B.; Steplewski, K.; Zembryki, D.; Oliva, C.; Roychowdhury, D.; Paoletti, P.; Winer, E. P. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer Clin. Cancer Res. 2009, 15, 1452– 1459 DOI: 10.1158/1078-0432.CCR-08-1080[Crossref], [PubMed], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXitVOktLo%253D&md5=74b9997947af74996e9eb840a6ff9152Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast CancerLin, Nancy U.; Dieras, Veronique; Paul, Devchand; Lossignol, Dominique; Christodoulou, Christos; Stemmler, Hans-Joachim; Roche, Henri; Liu, Minetta C.; Greil, Richard; Ciruelos, Eva; Loibl, Sibylle; Gori, Stefania; Wardley, Andrew; Yardley, Denise; Brufsky, Adam; Blum, Joanne L.; Rubin, Stephen D.; Dharan, Bernie; Steplewski, Klaudia; Zembryki, Denise; Oliva, Cristina; Roychowdhury, Debasish; Paoletti, Paolo; Winer, Eric P.Clinical Cancer Research (2009), 15 (4), 1452-1459CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)PURPOSE: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clin. challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was assocd. with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. Exptl. Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as ≥50% volumetric redn. of CNS lesion(s) in the absence of increasing steroid use, progressive neurol. signs and symptoms, or progressive extra-CNS disease. RESULTS: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were obsd. in 6% of patients. In an exploratory anal., 21% of patients experienced a ≥20% volumetric redn. in their CNS lesions. An assocn. was obsd. between volumetric redn. and improvement in progression-free survival and neurol. signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a ≥20% volumetric redn. in their CNS lesions. CONCLUSIONS: This study confirms the modest CNS antitumor activity of lapatinib. Addnl. responses were obsd. with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.
- 185Medina, P. J.; Goodin, S. Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases Clin. Ther. 2008, 30, 1426– 1447 DOI: 10.1016/j.clinthera.2008.08.008[Crossref], [PubMed], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtF2rtLfL&md5=e2e7505d278f03060c4bf664994f1ae1Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinasesMedina, Patrick J.; Goodin, SusanClinical Therapeutics (2008), 30 (8), 1426-1447CODEN: CLTHDG; ISSN:0149-2918. (Excerpta Medica, Inc.)A review. Background: Lapatinib, the first dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, was approved by the US Food and Drug Administration (FDA) in 2007. It is indicated for use in combination with capecitabine for the treatment of patients with advanced breast cancer or metastatic breast cancer (MBC) whose tumors overexpress HER2 (ErbB2) and who have received previous treatment that included an anthracycline, a taxane, and trastuzumab. Objective: This review summarizes the pharmacol., pharmacokinetics, clin. efficacy, and safety profile of lapatinib, and its current and potential role in the treatment of breast cancer and other malignancies. Methods: Relevant English-language publications were identified through searches of MEDLINE (1966-May 2008), the American Society of Clin. Oncol. abstrs. database (2000-2007), abstrs. from the San Antonio Breast Cancer Symposium (2005-2007), and the FDA Web site (Jan. 2008). Search terms included lapatinib, GW572016, HER2, EGFR, receptor tyrosine kinase, dual-receptor blockade, adverse events, and clin. trials. Results: The Tmax of lapatinib after oral administration is 3 to 4 h. Dividing the dose or administering it with food, particularly a high-fat meal, increases the AUC >2-fold. Lapatinib is metabolized primarily by the cytochrome P 450 3A4 isoenzyme, with 1 metabolite remaining active against EGFR but not HER2. Due to drug accumulation, the t1/2 of lapatinib is 24 h with continuous dosing. In a Phase III trial comparing lapatinib and capecitabine with capecitabine alone in women with HER2-pos., locally advanced breast cancer or MBC that had progressed after treatment with an anthracycline, a taxane, and trastuzumab, the combination of lapatinib and capecitabine was assocd. with a numeric improvement in response rate compared with capecitabine alone (22% vs 14%, resp.; P = NS) and a significant increase in time to progression (6.2 vs 4.3 mo; hazard ratio = 0.57; 95% CI, 0.43-0.77; P < 0.001). Lapatinib has been reported to have antitumor activity in Phase II trials when used as first-line therapy for MBC, in patients with inflammatory breast cancer, and in patients with central nervous system metastases. Phase II trials in other solid tumor types found modest activity. The approved dosing of lapatinib is 1250 mg PO QD given continuously in combination with capecitabine 2000 mg/m2 daily administered in 2 divided doses on days 1 to 14 of a 21-day cycle. The most common clin. toxicities of all grades assocd. with lapatinib used in combination with capecitabine in the pivotal clin. trial were diarrhea (65%), hand-foot syndrome (53%), nausea (44%), rash (29%), and fatigue (24%). Cardiac toxicity appears to be less frequent with lapatinib than with trastuzumab. Conclusions: Lapatinib is a dual inhibitor of the EGFR and HER2 tyrosine kinases. It is approved by the FDA for use in combination with capecitabine for the treatment of HER2-pos. MBC that has progressed with std. treatment. In clin. trials, this combination was assocd. with a significant improvement in the time to progression in patients with MBC. Lapatinib's efficacy in other malignancies that overexpress EGFR and/or HER2 is under evaluation.
- 186Taskar, K. S.; Rudraraju, V.; Mittapalli, R. K.; Samala, R.; Thorsheim, H. R.; Lockman, J.; Gril, B.; Hua, E.; Palmieri, D.; Polli, J. W.; Castellino, S.; Rubin, S. D.; Lockman, P. R.; Steeg, P. S.; Smith, Q. R. Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer Pharm. Res. 2012, 29, 770– 781 DOI: 10.1007/s11095-011-0601-8[Crossref], [PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtleqsLbN&md5=93de4680e8dcd3b0ee065ac002948ab7Lapatinib Distribution in HER2 Overexpressing Experimental Brain Metastases of Breast CancerTaskar, Kunal S.; Rudraraju, Vinay; Mittapalli, Rajendar K.; Samala, Ramakrishna; Thorsheim, Helen R.; Lockman, Julie; Gril, Brunilde; Hua, Emily; Palmieri, Diane; Polli, Joseph W.; Castellino, Stephen; Rubin, Stephen D.; Lockman, Paul R.; Steeg, Patricia S.; Smith, Quentin R.Pharmaceutical Research (2012), 29 (3), 770-781CODEN: PHREEB; ISSN:0724-8741. (Springer)Lapatinib, a small mol. EGFR/HER2 inhibitor, partially inhibits the outgrowth of HER2+ brain metastases in preclin. models and in a subset of CNS lesions in clin. trials of HER2+ breast cancer. We investigated the ability of lapatinib to reach therapeutic concns. in the CNS following 14C-lapatinib administration (100 mg/kg p.o. or 10 mg/kg, i.v.) to mice with MDA-MD-231-BR-HER2 brain metastases of breast cancer. Drug concns. were detd. at differing times after administration by quant. autoradiog. and chromatog. 14C-Lapatinib concn. varied among brain metastases and correlated with altered blood-tumor barrier permeability. On av., brain metastasis concn. was 7-9-fold greater than surrounding brain tissue at 2 and 12 h after oral administration. However, av. lapatinib concn. in brain metastases was still only 10-20% of those in peripheral metastases. Only in a subset of brain lesions (17%) did lapatinib concn. approach that of systemic metastases. No evidence was found of lapatinib resistance in tumor cells cultured ex vivo from treated brains. Results show that lapatinib distribution to brain metastases of breast cancer is partially restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies between tumors.
- 187Polli, J. W.; Olson, K. L.; Chism, J. P.; St. John-Williams, L.; Yeager, R. L.; Woodard, S. M.; Otto, V.; Castellino, S.; Demby, V. E. An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016 Drug Metab. Dispos. 2009, 37, 439– 442 DOI: 10.1124/dmd.108.024646
- 188Morikawa, A.; Peereboom, D. M.; Thorsheim, H. R.; Samala, R.; Balyan, R.; Murphy, C. G.; Lockman, P. R.; Simmons, A.; Weil, R. J.; Tabar, V.; Steeg, P. S.; Smith, Q. R.; Seidman, A. D. Capcitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study Neuro-Oncology 2015, 17, 289– 295 DOI: 10.1093/neuonc/nou141
- 189Schroeder, R. L.; Stevens, C. L.; Sridhar, J. Small molecule tyrosine kinase inhibitors of ErbB2/HER2/Neu in the treatment of aggressive breast cancer Molecules 2014, 19, 15196– 15212 DOI: 10.3390/molecules190915196[Crossref], [PubMed], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslSitLzF&md5=6b2f45be989c622b9a8d3dd7fd3f0146Small molecule tyrosine kinase inhibitors of ErbB2/HER2/Neu in the treatment of aggressive breast cancerSchroeder, Richard L.; Stevens, Cheryl L.; Sridhar, JayalakshmiMolecules (2014), 19 (9), 15196-15212, 17 pp.CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. The human epidermal growth factor receptor 2 (HER2) is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play crit. roles in the signal transduction cascade in a myriad of biochem. pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-pos. breast cancer. Existing therapies such as trastuzumab (Herceptin) and lapatinib (Tyverb/Tykerb), a monoclonal antibody inhibitor and a dual EGFR/HER2 kinase inhibitor, resp., are currently used in the treatment of HER2-pos. cancers, although issues with high recurrence and acquired resistance still remain. Small mol. tyrosine kinase inhibitors provide attractive therapeutic targets, as they are able to block cell signaling assocd. with many of the proposed mechanisms for HER2 resistance. In this regard we aim to present a review on the available HER2 tyrosine kinase inhibitors, as well as those currently in development. The use of tyrosine kinase inhibitors as sequential or combinatorial therapeutic strategies with other HER family inhibitors is also discussed.
- 190Feldinger, K.; Kong, A. Profile of neratinib and its potential in the treatment of breast cancer Breast Cancer: Targets Ther. 2015, 7, 147– 162 DOI: 10.2147/BCTT.S54414[Crossref], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnsFCht7c%253D&md5=599b49c22d664816005fc555b9ef3384Profile of neratinib and its potential in the treatment of breast cancerFeldinger, Katharina; Kong, AnthonyBreast Cancer: Targets and Therapy (2015), 7 (), 147-162CODEN: BCTTA9; ISSN:1179-1314. (Dove Medical Press Ltd.)The HER (ErbB) receptor tyrosine kinase receptors are implicated in many cancers and several anti-HER treatments are now approved. In recent years, a new group of compds. that bind irreversibly to the ATP binding pocket of HER receptors have been developed. One of these compds., neratinib, has passed preclin. phases and is currently undergoing various clin. trials. This manuscript reviews the preclin. as well as clin. data on neratinib. As a pan-HER inhibitor, this irreversible tyrosine kinase inhibitor binds and inhibits the tyrosine kinase activity of epidermal growth factor receptors, EGFR (or HER1), HER2 and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib has been shown to be effective against HER2-overexpressing or mutant tumors in vitro and in vivo. Neratinib is currently being investigated in various clin. trials in breast cancers and other solid tumors, including those with HER2 mutation. Earlier studies have already shown promising clin. activity for neratinib. However, more translational research is required to investigate biomarkers that could help to predict response and resistance for selection of appropriate patients for treatment with neratinib, either as monotherapy or in combination with other drug(s).
- 191Dinkel, V.; Anderson, D.; Winski, S.; Winkler, J.; Koch, K.; Lee, P. A. Abstract 852: ARRY-380, a potent, small molecule inhibitor of ErbB2, increases survival in intracranial ErbB2+ xenograft models in mice Cancer Res. 2012, 72 (Suppl.) 852 DOI: 10.1158/1538-7445.AM2012-852
- 192Freedman, R. A.; Gelman, R. S.; Wefel, J. S.; Melisko, M. E.; Hess, K. R.; Connolly, R. M.; Van Poznak, C. H.; Niravath, P. A.; Puhalla, S. L.; Ibrahim, N.; Blackwell, K. L.; Liu, M. C.; Lowe, A.; Agar, N. Y. R.; Ryabin, N.; Farooq, S.; Lawler, E.; Rimawi, M. F.; Krop, I. E.; Wolff, A. C.; Winer, E. P.; Lin, N. U. Translational Breast Cancer Research Consortium (TBCRC) 022: A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases J. Clin. Oncol. 2016, 34, 945– 952 DOI: 10.1200/JCO.2015.63.0343[Crossref], [PubMed], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28nmtlOgsA%253D%253D&md5=88dba0840a4214b2abf63bc4765c669eTranslational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain MetastasesFreedman Rachel A; Gelman Rebecca S; Wefel Jeffrey S; Melisko Michelle E; Hess Kenneth R; Connolly Roisin M; Van Poznak Catherine H; Niravath Polly A; Puhalla Shannon L; Ibrahim Nuhad; Blackwell Kimberly L; Moy Beverly; Herold Christina; Liu Minetta C; Lowe Alarice; Agar Nathalie Y R; Ryabin Nicole; Farooq Sarah; Lawler Elizabeth; Rimawi Mothaffar F; Krop Ian E; Wolff Antonio C; Winer Eric P; Lin Nancy UJournal of clinical oncology : official journal of the American Society of Clinical Oncology (2016), 34 (9), 945-52 ISSN:.PURPOSE: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. PATIENTS AND METHODS: Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders. RESULTS: Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. CONCLUSION: Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.
- 193Roche, S.; Pedersen, K.; Dunne, G.; Collins, D.; Devery, A.; Crown, J.; Clynes, M.; O’Connor, R. Pharmacological interactions of TKIs with the P-gp drug transport protein J. Clin. Oncol. 2012, 30 (Suppl.) 2536
- 194Metzger-Filho, O.; Barry, W. T.; Krop, I. E.; Younger, W. J.; Lawler, E. S.; Winer, E. P.; Lin, N. U. Phase I dose-escalation trial of ONT-380 in combination with trastuzumab in participants with brain metastases from HER2+ breast cancer J. Clin. Oncol. 2014, 32 (Suppl.) TPS660
- 195Ishikawa, T.; Seto, M.; Banno, H.; Kawakita, Y.; Oorui, M.; Taniguchi, T.; Ohta, Y.; Tamura, T.; Nakayama, A.; Miki, H.; Kamiguchi, H.; Tanaka, T.; Habuka, N.; Sogabe, S.; Yano, J.; Aertgeerts, K.; Kamiyama, K. Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold J. Med. Chem. 2011, 54, 8030– 8050 DOI: 10.1021/jm2008634[ACS Full Text], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlajur7M&md5=ce030ac133a1c0ff7cb78b269ff85987Design and Synthesis of Novel Human Epidermal Growth Factor Receptor 2 (HER2)/Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing a Pyrrolo[3,2-d]pyrimidine ScaffoldIshikawa, Tomoyasu; Seto, Masaki; Banno, Hiroshi; Kawakita, Youichi; Oorui, Mami; Taniguchi, Takahiko; Ohta, Yoshikazu; Tamura, Toshiya; Nakayama, Akiko; Miki, Hiroshi; Kamiguchi, Hidenori; Tanaka, Toshimasa; Habuka, Noriyuki; Sogabe, Satoshi; Yano, Jason; Aertgeerts, Kathleen; Kamiyama, KeijiJournal of Medicinal Chemistry (2011), 54 (23), 8030-8050CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivs., e.g. I, capable of fitting into the receptors' ATP binding site. Among the prepd. compds., I showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of I with both HER2 and EGFR demonstrated that I interacts with the expected residues in their resp. ATP pockets. Furthermore, reflecting its good oral bioavailability, I exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report I (TAK-285) as a promising candidate for clin. development as a novel HER2/EGFR dual kinase inhibitor.
- 196Erdo, F.; Gordon, J.; Wu, J. T.; Sziraki, I. Verification of brain penetration of the unbound fraction of a novel HER2/EGFR dual kinase inhibitor (TAK-285) by microdialysis in rats Brain Res. Bull. 2012, 87, 413– 419 DOI: 10.1016/j.brainresbull.2012.01.002[Crossref], [PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1Gqtrw%253D&md5=88acff4f029db2032dfae93bff601d18Verification of brain penetration of the unbound fraction of a novel HER2/EGFR dual kinase inhibitor (TAK-285) by microdialysis in ratsErdo, Franciska; Gordon, Justin; Wu, Jing-Tao; Sziraki, IstvanBrain Research Bulletin (2012), 87 (4-5), 413-419CODEN: BRBUDU; ISSN:0361-9230. (Elsevier Inc.)TAK-285, an investigational, orally active HER2/EGRF inhibitor is in clin. development for potential use in HER2 over-expressing metastatic breast cancer. The objective of the present work was to verify the presence of unbound TAK-285 in the rat brain after oral administration by a microdialysis technique with simultaneous sampling of blood and brain. In a pilot microdialysis expt. no detectable amt. of TAK-285 was found in the brain dialyzate samples after oral administration of the drug (50 mg/kg). A conventional pharmacokinetic study was performed simultaneously with the pilot microdialysis study using the same dosing suspension. TAK-285 was detected in the brain even at the last time point when the samples were taken from the animal at the end-point of the microdialysis expt. The apparent absence of TAK-285 in blood and brain dialyzate samples might be explained by a very low recovery of microdialysis probes for TAK-285 and/or by the adsorption of the compd. to the outflow tubing of the microdialysis probes. Results of an in vitro recovery study with TAK-285 were indicative of the strong adsorption of the compd. to the microdialysis tubings. Adding bovine serum albumin (4%, w/v) in perfusion fluids and reducing perfusion flow rate (from 1.0 μL/min to 0.5 μL/min) in in vitro expts. substantially improved the detectability of TAK-285 in dialyzate samples. Application of new perfusion conditions resulted in a manifold increase of the relative recovery of the microdialysis set-up for TAK-285 (from 1.6% to 47%). Subsequent in vivo microdialysis expts. were performed using the modified perfusion conditions in animals dosed with TAK-285 (75 mg/kg, p.o.). Detectable level of unbound TAK-285 was found in the extracellular space in the brain as long as 24-28 h after administration of the drug. The brain-to-blood ratios of the unbound TAK-285 were 0.18 and 0.24 (calcd. from the Cmax values or from the area under the curve [AUC] values) similarly to the brain-to-blood ratios of total TAK-285. On the basis of substantial brain penetration of unbound TAK-285, it is concluded that TAK-285 might have the potential in the treatment of brain metastases of HER2 over-expressing metastatic breast cancer. The methodol. approach described here might help to solve similar problems in detn. of brain penetration of other substances with strong adsorption to the tubing of microdialysis setups.
- 197Nakayama, A.; Takagi, S.; Yusa, T.; Yaguchi, M.; Hayashi, A.; Tamura, T.; Kawakita, Y.; Ishikawa, T.; Ohta, Y. Antitumor activity of TAK-285, an investigational, non-Pgp substrate HER2/EGFR kinase inhibitor, in cultured tumor cells, mouse and rat xenograft tumors, and in an HER2-positive brain metastasis model J. Cancer 2013, 4, 557– 565 DOI: 10.7150/jca.6689[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisVejtr0%253D&md5=d680347de9dd1a09135be86da06307deAntitumor activity of TAK-285, an investigational, non-Pgp substrate HER2/EGFR kinase inhibitor, in cultured tumor cells, mouse and rat xenograft tumors, and in an HER2-positive brain metastasis modelNakayama, Akiko; Takagi, Shinji; Yusa, Tadashi; Yaguchi, Masahiro; Hayashi, Akira; Tamura, Toshiya; Kawakita, Youichi; Ishikawa, Tomoyasu; Ohta, YoshikazuJournal of Cancer (Wyoming, Australia) (2013), 4 (7), 557/1-557/9CODEN: JCWAAL; ISSN:1837-9664. (Ivyspring International Publisher Pty Ltd.)Breast cancer therapy has improved following the development of drugs with specific mol. targets, exemplified by inhibitors of human epidermal growth factor receptor-2 (HER2) or epidermal growth factor receptor (EGFR) such as trastuzumab and lapatinib. However, these drugs have little effect on brain metastasis due to the combined effects of poor penetration of the blood-brain barrier and their removal from the central nervous system (CNS) by the p-glycoprotein (Pgp) drug efflux pump. We investigated the effects of TAK-285, a novel, investigational, dual EGFR/HER2 inhibitor that has been shown to penetrate the CNS and has comparable inhibitory efficacy to lapatinib which is a known Pgp substrate. Tested against a panel of 96 kinases, TAK-285 showed specificity for inhibition of HER family kinases. Unlike lapatinib, TAK-285 is not a substrate for Pgp efflux. In mouse and rat xenograft tumor models, TAK-285 showed antitumor activity against cancers that expressed HER2 or EGFR. TAK-285 was as effective as lapatinib in antitumor activity in a mouse s.c. BT-474 breast cancer xenograft model. TAK-285 was examd. in a model of breast cancer brain metastasis using direct intracranial injection of BT-474-derived luciferase-expressing cells and showed greater inhibition of brain tumor growth compared to animals treated with lapatinib. Our studies suggest that investigational drugs such as TAK-285 that have strong antitumor activity and are not Pgp substrates may be useful in the development of agents with the potential to treat brain metastases.
- 198Kalous, O.; Conklin, D.; Desai, A. J.; O’Brien, N. A.; Ginther, C.; Anderson, L.; Cohen, D. J.; Britten, C. D.; Taylor, I.; Christensen, J. G.; Slamon, D. J.; Finn, R. S. Dacomitinib (PF-00299804), an irreversible Pan-HER inhibitor, inhibits proliferation of HER2-amplified breast cancer cell lines resistant to trastuzumab and lapatinib Mol. Cancer Ther. 2012, 11, 1978– 1987 DOI: 10.1158/1535-7163.MCT-11-0730[Crossref], [PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlWhsrvI&md5=b2b0677cbecb66e1e629742adffb0782Dacomitinib (PF-00299804), an Irreversible Pan-HER Inhibitor, Inhibits Proliferation of HER2-Amplified Breast Cancer Cell Lines Resistant to Trastuzumab and LapatinibKalous, Ondrej; Conklin, Dylan; Desai, Amrita J.; O'Brien, Neil A.; Ginther, Charles; Anderson, Lee; Cohen, David J.; Britten, Carolyn D.; Taylor, Ian; Christensen, James G.; Slamon, Dennis J.; Finn, Richard S.Molecular Cancer Therapeutics (2012), 11 (9), 1978-1987CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)The human EGF (HER) family of receptors has been pursued as therapeutic targets in breast cancer and other malignancies. Trastuzumab and lapatinib are std. treatments for HER2-amplified breast cancer, but a significant no. of patients do not respond or develop resistance to these drugs. Here we evaluate the in vitro activity of dacomitinib (PF-00299804), an irreversible small mol. pan-HER inhibitor, in a large panel of human breast cancer cell lines with variable expression of the HER family receptors and ligands, and with variable sensitivity to trastuzumab and lapatinib. Forty-seven human breast cancer and immortalized breast epithelial lines representing the known mol. subgroups of breast cancer were treated with dacomitinib to det. IC50 values. HER2-amplified lines were far more likely to respond to dacomitinib than nonamplified lines (RR, 3.39; P < 0.0001). Furthermore, HER2 mRNA and protein expression were quant. assocd. with response. Dacomitinib reduced the phosphorylation of HER2, EGFR, HER4, AKT, and ERK in the majority of sensitive lines. Dacomitinib exerted its antiproliferative effect through a combined G0-G1 arrest and an induction of apoptosis. Dacomitinib inhibited growth in several HER2-amplified lines with de novo and acquired resistance to trastuzumab. Dacomitinib maintained a high activity in lines with acquired resistance to lapatinib. This study identifies HER2-amplified breast cancer lines as most sensitive to the antiproliferative effect of dacomitinib and provides a strong rationale for its clin. testing in HER2-amplified breast cancers resistant to trastuzumab and lapatinib. Mol Cancer Ther; 11(9); 1978-87. ©2012 AACR.
- 199Wong, T. W.; Lee, F. Y.; Yu, C.; Luo, F. R.; Oppenheimer, S.; Zhang, H.; Smykla, R. A.; Mastalerz, H.; Fink, B. E.; Hunt, J. T.; Gavai, A. V.; Vite, G. D. Preclinical antitumor activity of BMS-599626, a pan-HER kinase inhibitor that inhibits HER1/HER2 homodimer and heterodimer signaling Clin. Cancer Res. 2006, 12, 6186– 6193 DOI: 10.1158/1078-0432.CCR-06-0642[Crossref], [PubMed], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFWhsbbK&md5=a8350e2eb304a091fa82f1159e44c119Preclinical Antitumor Activity of BMS-599626, a pan-HER Kinase Inhibitor That Inhibits HER1/HER2 Homodimer and Heterodimer SignalingWong, Tai W.; Lee, Francis Y.; Yu, Chiang; Luo, Feng R.; Oppenheimer, Simone; Zhang, Hongjian; Smykla, Richard A.; Mastalerz, Harold; Fink, Brian E.; Hunt, John T.; Gavai, Ashvinikumar V.; Vite, Gregory D.Clinical Cancer Research (2006), 12 (20, Pt. 1), 6186-6193CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: The studies described here are intended to characterize the ability of BMS-599626, a small-mol. inhibitor of the human epidermal growth factor receptor (HER) kinase family, to modulate signaling and growth of tumor cells that depend on HER1 and/or HER2. Exptl. Design: The potency and selectivity of BMS-599626 were assessed in biochem. assays using recombinant protein kinases, as well as in cell proliferation assays using tumor cell lines with varying degrees of dependence on HER1 or HER2 signaling. Modulation of receptor signaling was detd. in cell assays by Western blot analyses of receptor autophosphorylation and downstream signaling. The ability of BMS-599626 to inhibit receptor heterodimer signaling in tumor cells was studied by receptor coimmunopptn. Antitumor activity of BMS-599626 was evaluated using a no. of different xenograft models that represent a spectrum of human tumors with HER1 or HER2 overexpression. Results: BMS-599626 inhibited HER1 and HER2 with IC50 of 20 and 30 nmol/L, resp., and was highly selective when tested against a broad panel of diverse protein kinases. Biochem. studies suggested that BMS-599626 inhibited HER1 and HER2 through distinct mechanisms. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC50 in the range of 0.24 to 1 μmol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling. BMS-599626 had antitumor activity in models that overexpress HER1 (GEO), as well as in models that have HER2 gene amplification (KPL4) or overexpression (Sal2), and there was good correlation between the inhibition of receptor signaling and antitumor activity. Conclusions: BMS-599626 is a highly selective and potent inhibitor of HER1 and HER2 kinases and inhibits tumor cell proliferation through modulation of receptor signaling. BMS-599626 inhibits HER1/HER2 receptor heterodimerization and provides an addnl. mechanism of inhibiting tumors in which receptor coexpression and heterodimerization play a major role in driving tumor growth. The preclin. data support the advancement of BMS-599626 into clin. development for the treatment of cancer.
- 200Desjardins, A.; Reardon, D. A.; Vredenburgh, J. J.; Peters, K.; Trikha, M.; James, J.; Gardner, M.; Brickhouse, A.; Herndon, J. E.; Friedman, H. S. A pharmacokinetic study of AC48 administered twice daily in patients with surgically resectable, recurrent malignant glioma (MG) not on enzyme-inducing antiepileptic drug (EIAED) J. Clin. Oncol. 2011, 29 (Suppl.) 2070
- 201Traxler, P.; Allegrini, P. R.; Brandt, R.; Brueggen, J.; Cozens, R.; Fabbro, D.; Grosios, K.; Lane, H. A.; McSheehy, P.; Mestan, J.; Meyer, T.; Tang, C.; Wartmann, M.; Wood, J.; Caravatti, G. AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity Cancer Res. 2004, 64, 4931– 4941 DOI: 10.1158/0008-5472.CAN-03-3681
- 202Meco, D.; Servidei, T.; Zannoni, G. F.; Martinelli, E.; Prisco, M. G.; de Waure, C.; Riccardi, R. Dual inhibitor AEE788 reduces tumor growth in preclinical models of medulloblastoma Trans. Oncol. 2010, 3, 326– 335 DOI: 10.1593/tlo.10163[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cfmvVWiug%253D%253D&md5=dfd2a6b42009efdd77401ea45f53be7fDual Inhibitor AEE788 Reduces Tumor Growth in Preclinical Models of MedulloblastomaMeco Daniela; Servidei Tiziana; Zannoni Gian Franco; Martinelli Enrica; Prisco Maria Grazia; de Waure Chiara; Riccardi RiccardoTranslational oncology (2010), 3 (5), 326-35 ISSN:.Medulloblastoma is the most frequent malignant pediatric brain tumor with a dismal prognosis in 30% of cases. We examined the activity of AEE788, a dual inhibitor of human epidermal receptor (HER) 1/2 and vascular endothelial growth factor receptor (VEGFR) 1/2, in medulloblastoma preclinical models. Established lines (Daoy and D283), chemoresistant (Daoy(Pt)), and ectopically HER2-overexpressing (Daoy(HER2)) cells expressed diverse levels of total and activated AEE788 target receptors. In vitro, AEE788 inhibited cell proliferation (IC(50) from 1.7 to 3.8 μM) and prevented epidermal growth factor- and neuregulin-induced HER1, HER2, and HER3 activation. Inhibition of Akt paralleled that of HER receptors. In vivo, AEE788 growth inhibited Daoy, Daoy(Pt), and Daoy(HER2) xenografts by 51%, 45%, and 72%, respectively. Immunohistochemical analysis of mock- and HER2-transfected xenografts revealed that the latter showed, along with high HER2 expression, high VEGFR2 staining in tumor and endothelial cells and increased expression of the endothelial marker CD31. AEE788 reduced the activation of target receptors and angiogenesis. In 21 primary medulloblastoma, HER2 expression significantly correlated (P < .01) with VEGFR2 (r = 0.56) and VEGF (r = 0.61). In conclusion, AEE788 shows similar growth-suppressive activities in chemosensitive and chemoresistant medulloblastoma cells in vitro and in vivo. Ectopic HER2 overexpression sensitizes cells to AEE788 in vivo, but not in vitro, possibly through host-mediated processes. Together with the experimental data, the finding that HER2 positively correlates with VEGFR2 and VEGF in human medulloblastoma specimens indicates HER2-overexpressing medulloblastoma as the subset that most likely might benefit from AEE788 treatment.
- 203Goudar, R. K.; Shi, Q.; Hjelmeland, M. D.; Keir, S. T.; McLendon, R. E.; Wikstrand, C. J.; Reese, E. D.; Conrad, C. A.; Traxler, P.; Lane, H. A.; Reardon, D. A.; Cavenee, W. K.; Wang, X. F.; Bigner, D. D.; Friedman, H. S.; Rich, J. N. Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition Mol. Cancer Ther. 2005, 4, 101– 112[PubMed], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXksFyqsA%253D%253D&md5=6b3da386f418d97000bc1a6ac9dff42bCombination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibitionGoudar, Ranjit K.; Shi, Qing; Hjelmeland, Mark D.; Keir, Stephen T.; McLendon, Roger E.; Wikstrand, Carol J.; Reese, Elizabeth D.; Conrad, Charles A.; Traxler, Peter; Lane, Heidi A.; Reardon, David A.; Cavenee, Webster K.; Wang, Xiao-Fan; Bigner, Darell D.; Friedman, Henry S.; Rich, Jeremy N.Molecular Cancer Therapeutics (2005), 4 (1), 101-112CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a single mol. target may slow tumor progression, but tumors are likely not dependent on a signal transduction pathway. Rather, malignant gliomas exhibit sustained mitogenesis and cell growth mediated in part through the effects of receptor tyrosine kinases and the mammalian target of rapamycin (mTOR). AEE788 is a novel orally active tyrosine kinase inhibitor that decreases the kinase activity assocd. with the epidermal growth factor receptor and, at higher concns., the vascular endothelial growth factor receptor 2 (kinase domain region). RAD001 (everolimus) is an orally available mTOR inhibitor structurally related to rapamycin. We hypothesized that combined inhibition of upstream epidermal growth factor receptor and kinase domain region receptors with AEE788 and inhibition of the downstream mTOR pathway with RAD001 would result in increased efficacy against gliomas compared with single-agent therapy. In vitro expts. showed that the combination of AEE788 and RAD001 resulted in increased rates of cell cycle arrest and apoptosis and reduced proliferation more than either agent alone. Combined AEE788 and RAD001 given orally to athymic mice bearing established human malignant glioma tumor xenografts resulted in greater tumor growth inhibition and greater increases in median survival than monotherapy. These studies suggest that simultaneous inhibition of growth factor receptor and mTOR pathways offer increased benefit in glioma therapy.
- 204Reardon, D. A.; Conrad, C. A.; Cloughesy, T.; Prados, M. D.; Friedman, H. S.; Aldape, K. D.; Mischel, P.; Xia, J.; DiLea, C.; Huang, J.; Mietlowski, W.; Dugan, M.; Chen, W.; Yung, W. K. A. Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients Cancer Chemother. Pharmacol. 2012, 69, 1507– 1518 DOI: 10.1007/s00280-012-1854-6[Crossref], [PubMed], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnvFOnsbY%253D&md5=cd6133b54e9d7e481af1dc42cd4917d2Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patientsReardon, David A.; Conrad, Charles A.; Cloughesy, Timothy; Prados, Michael D.; Friedman, Henry S.; Aldape, Kenneth D.; Mischel, Paul; Xia, Jane; DiLea, Clifford; Huang, Jerry; Mietlowski, William; Dugan, Margaret; Chen, Wei; Yung, W. K. AlfredCancer Chemotherapy and Pharmacology (2012), 69 (6), 1507-1518CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose Vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) play a significant role in glioblastoma angiogenesis and proliferation, making tyrosine kinase (TK) receptors logical targets for treatment. We evaluated AEE788, a reversible TK inhibitor that inhibits EGFR and VEGFR, in recurrent glioblastoma patients. Methods In this dose-escalation, phase I study, patients with recurrent glioblastoma received AEE788 once daily in 28-day cycles in stratified subgroups: those receiving (1) non-enzyme-inducing anticonvulsants drugs or no anticonvulsants (Group A) and (2) enzyme-inducing anticonvulsant drugs (Group B). A dose-expansion phase stratified patients by surgical eligibility. Primary objectives were to det. dose-limiting toxicity (DLT) and max. tolerated dose; secondary objectives included evaluating (1) safety/tolerability, (2) pharmacokinetics, and (3) preliminary antitumor activity. Results Sixty-four glioblastoma patients were enrolled. Two Group A patients experienced DLTs (proteinuria and stomatitis) at 550 mg; 550 mg was, therefore, the highest dose evaluated and dose limiting. One Group B patient receiving 800 mg experienced a DLT (diarrhea). The initially recommended dose for dose-expansion phase for Group A was 400 mg; addnl. patients received 250 mg to assess the hepatotoxicity. Most frequently reported adverse events (AEs) included diarrhea and rash. Serious AEs, most commonly grade 3/4 liver function test elevations, were responsible for treatment discontinuation in 17% of patients. AEE788 concns. were reduced by EIACD. The best overall response was stable disease (17%). Conclusions Continuous, once-daily AEE788 was assocd. with unacceptable toxicity and minimal activity for the treatment of recurrent glioblastoma. The study was, therefore, discontinued prematurely.
- 205Wissner, A.; Mansour, T. S. The development of HKI-272 and related compounds for the treatment of cancer Arch. Pharm. 2008, 341, 465– 477 DOI: 10.1002/ardp.200800009[Crossref], [PubMed], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVKnsb7E&md5=2e46d99ca74e297e6a7e860634bf096dThe development of HKI-272 and related compounds for the treatment of cancerWissner, Allan; Mansour, Tarek S.Archiv der Pharmazie (Weinheim, Germany) (2008), 341 (8), 465-477CODEN: ARPMAS; ISSN:0365-6233. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The development of HKI-272 and EKB-569 for the treatment of cancer is described. These compds. function as irreversible inhibitors of some members of the ErbB family of receptor tyrosine kinases. In particular, they target epidermal growth factor receptor (EGFR, also known as ErbB-1) and human epidermal growth factor receptor-2 (HER2, also known as ErbB-2). Both, HKI-272 and EKB-569 are 4-anilino-3-cyano quinoline derivs. that contain a 4-(dimethylamino)crotonamide Michael-acceptor group at the 6-position. These compds. inhibit the function of the target enzymes by forming a covalent interaction with a conserved cysteine residue located in the kinase domains of these proteins. The potential advantages of using irreversible inhibitors for this purpose are discussed. We summarize the recent findings concerning some somatic mutations in EGFR and their relevance with respect to the irreversible inhibitors. In particular, we highlight the findings that these irreversible inhibitors retain activity against tumors that have acquired a resistance to the reversible binding inhibitors gefitinib and erlotinib. The promising interim clin. trial results for HKI-272 and EKB-569 in treating colon, lung, and breast cancers are summarized.
- 206Hegedus, C.; Truta-Feles, K.; Antalffy, G.; Varady, G.; Nemet, K.; Ozvegy-Laczka, C.; Keri, G.; Orfi, L.; Szakacs, G.; Settleman, J.; Varadi, A.; Sarkadi, B. Interaction of the EGFR inhibitors gefitinib, vandetanib, pelitinib and neratinib with the ABCG2 multidrug transporter: implications for the emergence and reversal of cancer drug resistance Biochem. Pharmacol. 2012, 84, 260– 267 DOI: 10.1016/j.bcp.2012.04.010
- 207Jani, J. P.; Finn, R. S.; Campbell, M.; Coleman, K. G.; Connell, R. D.; Currier, N.; Emerson, E. O.; Floyd, E.; Harriman, S.; Kath, J. C.; Morris, J.; Moyer, J. D.; Pustilnik, L. R.; Rafidi, K.; Ralston, S.; Rossi, A. M. K.; Steyn, S. J.; Wagner, L.; Winter, S. M.; Bhattacharya, S. K. Discovery and pharmacologic characterization of CP-724,714, a selective ErbB2 tyrosine kinase inhibitor Cancer Res. 2007, 67, 9887– 9893 DOI: 10.1158/0008-5472.CAN-06-3559
- 208Feng, B.; Xu, J. J.; Bi, Y. A.; Mireles, R.; Davidson, R.; Duignan, D. B.; Campbell, S.; Kostrubsky, V. E.; Dunn, M. C.; Smith, A. R.; Wang, H. F. Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724,714 Toxicol. Sci. 2009, 108, 492– 500 DOI: 10.1093/toxsci/kfp033[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktFWjtrk%253D&md5=b5f3892f39f1460d1f33d11e16a683bdRole of Hepatic Transporters in the Disposition and Hepatotoxicity of a HER2 Tyrosine Kinase Inhibitor CP-724,714Feng, Bo; Xu, Jinghai J.; Bi, Yi-An; Mireles, Rouchelle; Davidson, Ralph; Duignan, David B.; Campbell, Scott; Kostrubsky, Vsevolod E.; Dunn, Margaret C.; Smith, Arthur R.; Wang, Huifen F.Toxicological Sciences (2009), 108 (2), 492-500CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)CP-724,714, a potent and selective orally active HER2 tyrosine kinase inhibitor, was discontinued from clin. development due to unexpected hepatotoxicity in cancer patients. Based on the clin. manifestation of the toxicity, CP-724,714 likely exerted its hepatotoxicity via both hepatocellular injury and hepatobiliary cholestatic mechanisms. The direct cytotoxic effect, hepatobiliary disposition of CP-724,714, and its inhibition of active canalicular transport of bile constituents were evaluated in established human hepatocyte models and in vitro transporter systems. CP-724,714 exhibited direct cytotoxicity using human hepatocyte imaging assay technol. with mitochondria identified as a candidate organelle for its off-target toxicity. Addnl., CP-724,714 was rapidly taken up into human hepatocytes, partially via an active transport process, with an uptake clearance approx. fourfold higher than efflux clearance. The major human hepatic uptake transporter, OATP1B1, and efflux transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein, were involved in hepatobiliary clearance of CP-724,714. Furthermore, CP-724,714 displayed a concn.-dependent inhibition of cholyl-lysyl fluorescein and taurocholate (TC) efflux into canaliculi in cryopreserved and fresh cultured human hepatocytes, resp. Likewise, CP-724,714 inhibited TC transport in membrane vesicles expressing human bile salt export pump with an IC50 of 16μM. Finally, CP-724,714 inhibited the major efflux transporter in bile canaliculi, MDR1, with an IC50 of ∼28μM. These results suggest that inhibition of hepatic efflux transporters contributed to hepatic accumulation of drug and bile constituents leading to hepatocellular injury and hepatobiliary cholestasis. This study provides likely explanations for clin. obsd. adverse liver effects of CP-724,714.
- 209Cai, X.; Zhai, H. X.; Wang, J.; Forrester, J.; Qu, H.; Yin, L.; Lai, C. J.; Bao, R.; Qian, C. Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer J. Med. Chem. 2010, 53, 2000– 2009 DOI: 10.1021/jm901453q[ACS Full Text], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhslSgsb0%253D&md5=d4dc339f2fd750d52e511abf3dbf18bdDiscovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a Potent Multi-Acting HDAC, EGFR, and HER2 Inhibitor for the Treatment of CancerCai, Xiong; Zhai, Hai-Xiao; Wang, Jing; Forrester, Jeffrey; Qu, Hui; Yin, Ling; Lai, Cheng-Jung; Bao, Rudi; Qian, ChanggengJournal of Medicinal Chemistry (2010), 53 (5), 2000-2009CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compds. with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clin. development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC50 of 4.4, 2.4, and 15.7 nM, resp. In most tumor cell lines tested, 8 exhibits efficient antiproliferative activity with greater potency than vorinostat (SAHA), erlotinib, lapatinib, and combinations of vorinostat/erlotinib and vorinostat/lapatinib. In vivo, 8 promotes tumor regression or inhibition in various cancer xenograft models including nonsmall cell lung cancer (NSCLC), liver, breast, head and neck, colon, and pancreatic cancers. These results suggest that a single compd. that simultaneously inhibits HDAC, EGFR, and HER2 may offer greater therapeutic benefits in cancer over single-acting agents through the interference with multiple pathways and potential synergy among HDAC and EGFR/HER2 inhibitors.
- 210Barlaam, B.; Anderton, J.; Ballard, P.; Bradbury, R. H.; Hennequin, L. F. A.; Hickinson, D. M.; Kettle, J. G.; Kirk, G.; Klinowska, T.; Lambert-van der Brempt, C.; Trigwell, C.; Vincent, J.; Ogilvie, D. Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors ACS Med. Chem. Lett. 2013, 4, 742– 746 DOI: 10.1021/ml400146c
- 211Xie, H.; Lin, L.; Tong, L.; Jiang, Y.; Zheng, M.; Chen, Z.; Jiang, X.; Zhang, X.; Ren, X.; Qu, W.; Yang, Y.; Wan, H.; Chen, Y.; Zuo, J.; Jiang, H.; Geng, M.; Ding, J. AST1306, a novel irreversible inhibitor of the epidermal growth factor receptor 1 and 2, exhibits antitumor activity both in vitro and in vivo PLoS One 2011, 6, e21487 DOI: 10.1371/journal.pone.0021487
- 212(a) Fife, K. M.; Colman, M. H.; Stevens, G. N.; Firth, I. C.; Moon, D.; Shannon, K. F.; Harman, R.; Petersen-Schaefer, K.; Zacest, A. C.; Besser, M.; Milton, G. W.; McCarthy, W. H.; Thompson, J. F. Determinants of outcome in melanoma patients with cerebral metastases J. Clin. Oncol. 2004, 22, 1293– 1300 DOI: 10.1200/JCO.2004.08.140[Crossref], [PubMed], [CAS], Google Scholar212ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c7lslOktA%253D%253D&md5=1bed3bd78055cfda69f608c3cef92274Determinants of outcome in melanoma patients with cerebral metastasesFife K M; Colman M H; Stevens G N; Firth I C; Moon D; Shannon K F; Harman R; Petersen-Schaefer K; Zacest A C; Besser M; Milton G W; McCarthy W H; Thompson J FJournal of clinical oncology : official journal of the American Society of Clinical Oncology (2004), 22 (7), 1293-300 ISSN:0732-183X.PURPOSE: To analyze prognostic factors, effects of treatment, and survival for patients with cerebral metastases from melanoma. PATIENTS AND METHODS: All melanoma patients with cerebral metastases treated at the Sydney Melanoma Unit between 1952 and 2000 were identified. From 1985 to 2000, patients were diagnosed and treated using consistent modern techniques and this cohort was analyzed in detail. Multivariate analysis of prognostic factors for survival was performed. RESULTS: A total of 1137 patients with cerebral metastases were identified; 686 were treated between 1985 and 2000. For these 686 patients, the median time from primary diagnosis to cerebral metastasis was 3.1 years (range, 0 to 41 years). A total of 646 patients (94%) have died as a result of melanoma. The median survival from the time of diagnosis of cerebral metastasis was 4.1 months (range, 0 to 17.2 years). Treatment was as follows: surgery and postoperative radiotherapy, 158 patients; surgery alone, 47 patients; radiotherapy alone, 236 patients; and supportive care alone, 210 patients. Median survival according to treatment received for these four groups was 8.9, 8.7, 3.4, and 2.1 months, respectively; the differences between surgery and nonsurgery groups were statistically significant. On multivariate analysis, significant factors associated with improved survival were surgical treatment (P <.0001), no concurrent extracerebral metastases (P <.0001), younger age (P =.0007), and longer disease-free interval (P =.036). Prognostic factors analysis confirmed the important influence of patient selection on treatment received. CONCLUSION: This large series documents the characteristics of patients who developed cerebral metastases from melanoma. Median survival was dependent on treatment, which in turn was dependent on patient selection.(b) Sampson, J. H.; Carter, J. H.; Friedman, A. H.; Seigler, H. F. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma J. Neurosurg. 1998, 88, 11– 20 DOI: 10.3171/jns.1998.88.1.0011[Crossref], [PubMed], [CAS], Google Scholar212bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK1c%252FotVagtg%253D%253D&md5=19def8072a8f68d34fa042627f3ef7d0Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanomaSampson J H; Carter J H Jr; Friedman A H; Seigler H FJournal of neurosurgery (1998), 88 (1), 11-20 ISSN:0022-3085.UNLABELLED: Brain metastases are a common and devastating complication in patients with malignant melanoma. Therapeutic options for these patients are limited, and the prognosis is usually poor. OBJECT: A retrospective review of 6953 patients with melanoma treated at a single institution was undertaken to identify demographic factors associated with the development of clinically significant brain metastases in 702 of these patients and to determine the factors influencing the prognosis of this population to permit more informed recommendations regarding surgical therapy. METHODS: Factors found to be associated with the development of brain metastases included male gender, primary lesions located on mucosal surfaces or on the skin of the trunk or head and neck, thick or ulcerated primary lesions, and histological findings of acral lentiginous or nodular lesions. The overall median survival time of all patients with brain metastases was 113.2 days, and these metastases contributed to the death of 94.5% of the patients in this group. Patients with primary lesions located in the head or neck region had a significantly shorter survival time relative to other patients with brain metastases, whereas patients with a single brain metastasis, patients without lung or multiple other visceral metastases, and patients whose initial presentation with melanoma included a brain metastasis had a significantly better prognosis. The small group of patients who survived for more than 3 years was characterized by the presence of a surgically treated, single brain metastasis in the absence of other visceral metastatic disease. CONCLUSIONS: Although most patients with brain metastases resulting from melanoma have a dismal prognosis, some who are likely to survive for longer periods can be identified. In these patients surgical resection can significantly prolong meaningful survival. The decision to recommend surgery should be based primarily on the resectability of the brain metastases and on the status and number of other organs with metastatic lesions.
- 213Flaherty, K. T.; Yasothan, U.; Kirkpatrick, P. Vemurafenib Nat. Rev. Drug Discovery 2011, 10, 811– 812 DOI: 10.1038/nrd3579[Crossref], [PubMed], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlyis77I&md5=571edc546d25485f37890e3d62ea90a1VemurafenibFlaherty, Keith. T.; Yasothan, Uma; Kirkpatrick, PeterNature Reviews Drug Discovery (2011), 10 (11), 811-812CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. In August 2011 vemurafenib (Zelboraf; Daiichi Sankyo/Roche), an inhibitor of BRAF kinase, was approved by the US Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation.
- 214Rheault, T. R.; Stellwagen, J. C.; Adjabeng, G. M.; Hornberger, K. R.; Petrov, K. G.; Waterson, A. G.; Dickerson, S. H.; Mook, R. A.; Laquerre, S. G.; King, A. J.; Rossanese, O. W.; Arnone, M. R.; Smitheman, K. N.; Kane-Carson, L. S.; Han, C.; Moorthy, G. S.; Moss, K. G.; Uehling, D. E. Discovery of dabrafenib: a selective inhibitor of Raf kinases with antitumor activity against B-Raf-driven tumors ACS Med. Chem. Lett. 2013, 4, 358– 362 DOI: 10.1021/ml4000063[ACS Full Text], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXit1Sqtr4%253D&md5=4b26187120192c298ca89283e2871fe4Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven TumorsRheault, Tara R.; Stellwagen, John C.; Adjabeng, George M.; Hornberger, Keith R.; Petrov, Kimberly G.; Waterson, Alex G.; Dickerson, Scott H.; Mook, Robert A.; Laquerre, Sylvie G.; King, Alastair J.; Rossanese, Olivia W.; Arnone, Marc R.; Smitheman, Kimberly N.; Kane-Carson, Laurie S.; Han, Chao; Moorthy, Ganesh S.; Moss, Katherine G.; Uehling, David E.ACS Medicinal Chemistry Letters (2013), 4 (3), 358-362CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-RafV600E mutated enzyme has been obsd. in a no. of human tumors, including melanomas. Herein, we report the discovery and biol. evaluation of GSK2118436 (dabrafenib, I), a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-RafV600E human melanoma. GSK2118436 was identified as a development candidate, and early clin. results have shown significant activity in patients with B-Raf mutant melanoma.
- 215Hoeflich, K. P.; Merchant, M.; Orr, C.; Chan, J.; Den Otter, D.; Berry, L.; Kasman, I.; Koeppen, H.; Rice, K.; Yang, N. Y.; Engst, S.; Johnston, S.; Friedman, L. S.; Belvin, M. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition Cancer Res. 2012, 72, 210– 219 DOI: 10.1158/0008-5472.CAN-11-1515[Crossref], [PubMed], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVCltA%253D%253D&md5=40032bf35d5e6335856a645d5c331df8Intermittent Administration of MEK Inhibitor GDC-0973 plus PI3K Inhibitor GDC-0941 Triggers Robust Apoptosis and Tumor Growth InhibitionHoeflich, Klaus P.; Merchant, Mark; Orr, Christine; Chan, Jocelyn; Den Otter, Doug; Berry, Leanne; Kasman, Ian; Koeppen, Hartmut; Rice, Ken; Yang, Nai-Ying; Engst, Stefan; Johnston, Stuart; Friedman, Lori S.; Belvin, MarciaCancer Research (2012), 72 (1), 210-219CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Combinations of MAP/ERK kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors have shown promise in preclin. cancer models, leading to the initiation of clin. trials cotargeting these two key cancer signaling pathways. GDC-0973, a novel selective MEK inhibitor, and GDC-0941, a class I PI3K inhibitor, are in early stage clin. trials as both single agents and in combination. The discovery of these selective inhibitors has allowed investigation into the precise effects of combining inhibitors of two major signaling branches downstream of RAS. Here, we investigated multiple biomarkers in the mitogen-activated protein kinase (MAPK) and PI3K pathway to search for points of convergence that explain the increased apoptosis seen in combination. Using washout studies in vitro and alternate dosing schedules in mice, we showed that intermittent inhibition of the PI3K and MAPK pathway is sufficient for efficacy in BRAF and KRAS mutant cancer cells. The combination of GDC-0973 with the PI3K inhibitor GDC-0941 resulted in combination efficacy in vitro and in vivo via induction of biomarkers assocd. with apoptosis, including Bcl-2 family proapoptotic regulators. Therefore, these data suggest that continuous exposure of MEK and PI3K inhibitors in combination is not required for efficacy in preclin. cancer models and that sustained effects on downstream apoptosis biomarkers can be obsd. in response to intermittent dosing. Cancer Res; 72(1); 210-9.
- 216Abe, H.; Kikuchi, S.; Hayakawa, K.; Iida, T.; Nagahashi, N.; Maeda, K.; Sakamoto, J.; Matsumoto, N.; Miura, T.; Matsumura, K.; Seki, N.; Inaba, T.; Kawasaki, H.; Yamaguchi, T.; Kakefuda, R.; Nanayama, T.; Kurachi, H.; Hori, Y.; Yoshida, T.; Kakegawa, J.; Watanabe, Y.; Gilmartin, A. G.; Richter, M. C.; Moss, K. G.; Laquerre, S. G. Discovery of a highly potent and selective MEK inhibitor: GSK1120212 (JTP-74057 DMSO solvate) ACS Med. Chem. Lett. 2011, 2, 320– 324 DOI: 10.1021/ml200004g[ACS Full Text], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisFeksb0%253D&md5=0cb3bfa4e142b8d5ecc591e6792cd692Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate)Abe, Hiroyuki; Kikuchi, Shinichi; Hayakawa, Kazuhide; Iida, Tetsuya; Nagahashi, Noboru; Maeda, Katsuya; Sakamoto, Johei; Matsumoto, Noriaki; Miura, Tomoya; Matsumura, Koji; Seki, Noriyoshi; Inaba, Takashi; Kawasaki, Hisashi; Yamaguchi, Takayuki; Kakefuda, Reina; Nanayama, Toyomichi; Kurachi, Hironori; Hori, Yoshikazu; Yoshida, Takayuki; Kakegawa, Junya; Watanabe, Yoshihiro; Gilmartin, Aidan G.; Richter, Mark C.; Moss, Katherine G.; Laquerre, Sylvie G.ACS Medicinal Chemistry Letters (2011), 2 (4), 320-324CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) represents a promising strategy for the discovery of a new generation of anticancer chemotherapeutics. Our synthetic efforts, beginning from the lead compd. 2, were directed at improving antiproliferative activity against cancer cells as well as various drug properties. These efforts led to the discovery of N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethylsulfoxide solvate (GSK1120212, JTP-74057 DMSO solvate; 1), a selective and highly potent MEK inhibitor with improved drug properties. We further confirmed that the antiproliferative activity correlates with cellular MEK inhibition and obsd. significant antitumor activity with daily oral dosing of 1 in a tumor xenograft model. These qualities led to the selection of 1 for clin. development.
- 217Myung, J. K.; Cho, H.; Park, C.-K.; Kim, S. K.; Lee, S. H.; Park, S. H. Analysis of the BRAF V600E mutation in central nervous system tumors Transl. Oncol. 2012, 5, 430– 436 DOI: 10.1593/tlo.12328[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s3pvVKmtw%253D%253D&md5=5b658d1f30e6051ee480912ea87c77b8Analysis of the BRAF(V600E) Mutation in Central Nervous System TumorsMyung Jae Kyung; Cho Hwajin; Park Chul-Kee; Kim Seung-Ki; Lee Se-Hoon; Park Sung-HyeTranslational oncology (2012), 5 (6), 430-6 ISSN:.BRAF(V600E) mutations are involved in the development of melanoma, colon cancer, and papillary thyroid carcinoma. These mutations are also found in primary brain tumors at low to moderate frequencies. In this study, we investigated a series of brain tumors to determine the prevalence and associated clinicopathologic features of BRAF(V600E) mutations. By direct sequencing, we analyzed 223 brain tumors, including 51 gangliogliomas (GGs), 45 pilocytic astrocytomas (PAs), 12 pleomorphic xanthoastrocytomas (PXAs), 35 glioblastomas (GBs), 28 anaplastic astrocytomas (AAs), 44 oligodendroglial tumors (ODGs), 3 anaplastic oligoastrocytomas, and 5 diffuse astrocytomas. Thirty-six cases (16.1%) exhibited the BRAF(V600E) mutation, including 66.7% of PXAs, 23.5% of GGs, 15.6% of PAs, and 9.7% of the malignant gliomas; the latter included 14.3% of AAs, 8.6% of GBs, and 4.5% of ODGs. Copy number aberration at the 7q34 (BRAF) locus was found in 73.1% of PAs and 50% of PXAs. 9p Homozygous deletion was found in 66.7% of PXAs, but it was not correlated with the BRAF(V600E) mutation. Patients' age, sex, histologic grade, and progression-free survival were also not correlated with the BRAF(V600E) mutation. The BRAF(V600E) mutation in brain tumors did not have prognostic value but is certainly a diagnostic marker and therapeutic target, not only for pediatric low-grade gliomas but also for malignant gliomas, even though the rate of mutation was not high. These results should be verified in a larger study with more cases and a longer follow-up period to overcome the limitation of small sample size.
- 218Kieran, M. W. Targeting BRAF in pediatric brain tumors. In American Society of Clinical Oncology 2014 Educational Book; Dizon, D. S.; Pennell, N.; Burke, L.; Carter, D.; Dottellis, D., Eds.; American Society of Clinical Oncology: Alexandria, VA, 2014; pp e436– e440, DOI: DOI: 10.14694/EdBook_AM.2014.34.e436 .
- 219See, W. L.; Tan, I. L.; Mukherjee, J.; Nicolaides, T.; Pieper, R. O. Sensitivity of glioblastomas to clinically available MEK inhibitors is defined by neurofibromin 1 deficiency Cancer Res. 2012, 72, 3350– 3359 DOI: 10.1158/0008-5472.CAN-12-0334
- 220(a) McCubrey, J. A.; Steelman, L. S.; Chappell, W. H.; Abrams, S. L.; Franklin, R. A.; Montalto, G.; Cervello, M.; Libra, M.; Candido, S.; Malaponte, G.; Mazzarino, M. C.; Fagone, P.; Nicoletti, F.; Basecke, J.; Mijatovic, S.; Maksimovic-Ivanic, D.; Milella, M.; Tafuri, A.; Chiarini, F.; Evangelisti, C.; Cocco, L.; Martelli, A. M. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance Oncotarget 2012, 3, 1068– 1111 DOI: 10.18632/oncotarget.659(b) Huang, T.; Karsy, M.; Zhuge, J.; Zhong, M.; Liu, D. B-Raf and the inhibitors: from bench to bedside J. Hematol. Oncol. 2013, 6, 30 DOI: 10.1186/1756-8722-6-30[Crossref], [PubMed], [CAS], Google Scholar220bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXotFWrsLw%253D&md5=62c83f28798a093cf4be76376020721bB-Raf and the inhibitors: from bench to bedsideHuang, Tiangui; Karsy, Michael; Zhuge, Jian; Zhong, Minghao; Liu, DelongJournal of Hematology & Oncology (2013), 6 (), 30CODEN: JHOOAO; ISSN:1756-8722. (BioMed Central Ltd.)A review. The B-Raf protein is a key signaling mol. in the mitogen activated protein kinase (MAPK) signaling pathway and has been implicated in the pathogenesis of a variety of cancers. An important V600E mutation has been identified and can cause constitutive B-Raf activation. Recent studies have evaluated a variety of small mol. inhibitors targeting B-Raf, including PLX4032/vemurafenib, dabrafenib, LGX818, GDC0879, XL281, ARQ736, PLX3603 (RO5212054), and RAF265. Therapeutic resistance has been identified and various mechanisms described. This review also discussed the current understanding of B-Raf signaling mechanism, methods of mutation detection, treatment strategies as well as potential methods of overcoming therapeutic resistance.
- 221(a) Zhao, Y.; Adjei, A. A. The clinical development of MEK inhibitors Nat. Rev. Clin. Oncol. 2014, 11, 385– 400 DOI: 10.1038/nrclinonc.2014.83[Crossref], [PubMed], [CAS], Google Scholar221ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXosVyqtbo%253D&md5=c81e0a5f52a8d4d482b7d617901d67ebThe clinical development of MEK inhibitorsZhao, Yujie; Adjei, Alex A.Nature Reviews Clinical Oncology (2014), 11 (7), 385-400CODEN: NRCOAA; ISSN:1759-4774. (Nature Publishing Group)A review. Aberrant activation of the RAS-RAF-MEK-ERK1/2 pathway occurs in more than 30% of human cancers. As part of this pathway, MEK1 and MEK2 have crucial roles in tumorigenesis, cell proliferation and inhibition of apoptosis and, therefore, MEK1/2 inhibition is an attractive therapeutic strategy in a no. of cancers. Highly selective and potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed and assessed in numerous clin. studies over the past decade. These agents are not efficacious in a broad range of unselected cancers, although single-agent antitumor activity has been detected mainly in tumors that harbor mutations in genes encoding the members of the RAS and RAF protein families, such as certain melanomas. Combinations of MEK1/2 inhibitors and cytotoxic chemotherapy, and/or other targeted agents are being studied to expand the efficacy of this class of agents. Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for the future clin. development of MEK inhibitors. We discuss the clin. experience with MEK inhibitors to date, and consider the novel approaches to MEK-inhibitor therapy that might improve outcomes and lead to the wider use of such treatments.(b) Akinleye, A.; Furqan, M.; Mukhi, N.; Ravella, P.; Liu, D. MEK and the inhibitors: from bench to bedside J. Hematol. Oncol. 2013, 6, 27 DOI: 10.1186/1756-8722-6-27[Crossref], [PubMed], [CAS], Google Scholar221bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmvFejurg%253D&md5=8443b97a166e26e53bd0b81641ed2114MEK and the inhibitors: from bench to bedsideAkinleye, Akintunde; Furqan, Muhammad; Mukhi, Nikhil; Ravella, Pavan; Liu, DelongJournal of Hematology & Oncology (2013), 6 (), 27CODEN: JHOOAO; ISSN:1756-8722. (BioMed Central Ltd.)A review. Four distinct MAP kinase signaling pathways involving 7 MEK enzymes have been identified. MEK1 and MEK2 are the prototype members of MEK family proteins. Several MEK inhibitors are in clin. trials. Trametinib is being evaluated by FDA for the treatment of metastatic melanoma with BRAF V600 mutation. Selumetinib has been studied in combination with docetaxel in phase II randomized trial in previously treated patients with advanced lung cancer. Selumetinib group had better response rate and progression-free survival. This review also summarized new MEK inhibitors in clin. development, including pimasertib, refametinib, PD-0325901, TAK733, MEK162 (ARRY 438162), RO5126766, WX-554, RO4987655 (CH4987655), GDC-0973 (XL518) and AZD8330.(c) McDermott, L.; Qin, C. Allosteric MEK1/2 Inhibitors for the Treatment of Cancer: An Overview. J. Drug Res. Dev. 2015, 1, DOI: DOI: 10.16966/2470-1009.101 ; http://dx.doi.org/10.16966/2470-1009.101.
- 222(a) Rochet, N. M.; Dronca, R. S.; Kottschade, L. A.; Chavan, R. N.; Gorman, B.; Gilbertson, J. R.; Markovic, S. N. Melanoma brain metastases and vemurafenib: need for further investigation Mayo Clin. Proc. 2012, 87, 976– 981 DOI: 10.1016/j.mayocp.2012.07.006[Crossref], [PubMed], [CAS], Google Scholar222ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntlaqsQ%253D%253D&md5=7d8eb3392d87022d61d94698445591c2Melanoma brain metastases and vemurafenib: need for further investigationRochet, Nicole M.; Dronca, Roxana S.; Kottschade, Lisa A.; Chavan, Rahul N.; Gorman, Brian; Gilbertson, Julie R.; Markovic, Svetomir N.Mayo Clinic Proceedings (2012), 87 (10), 976-981CODEN: MACPAJ; ISSN:0025-6196. (Elsevier)Brain metastases are a major cause of morbidity and mortality in patients with advanced melanoma. With the development of targeted agents for the treatment of metastatic melanoma, a great deal of interest has focused on whether selective BRAF inhibitors may play a role in the treatment of brain metastases in lieu of or in addn. to surgery and/or radiation therapy. However, relatively little is known about the intracranial effectiveness of vemurafenib, the only US Food and Drug Administration-approved selective BRAF V600E inhibitor, because patients with brain metastases have historically been excluded from vemurafenib clin. trials. We describe 3 patients with BRAF V600E mutation metastatic melanoma in whom treatment with vemurafenib resulted in prompt extracranial disease response but progression of metastatic disease in the brain. Further, we discuss possible mechanisms responsible for the suboptimal central nervous system response obsd. in these patients and alternative therapies for patients with melanoma metastatic to the brain.(b) Gummadi, T.; Zhang, B. Y.; Valpione, S.; Kim, C.; Kottschade, L. A.; Mittapalli, R. K.; Chiarion-Sileni, V.; Pigozzo, J.; Elmquist, W. F.; Dudek, A. Impact of BRAF mutation and BRAF inhibition on melanoma brain metastases Melanoma Res. 2015, 25, 75– 79 DOI: 10.1097/CMR.0000000000000133[Crossref], [PubMed], [CAS], Google Scholar222bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFKqsbjK&md5=3570e6ac8c3f9b28c6ffb5766ea68fe0Impact of BRAF mutation and BRAF inhibition on melanoma brain metastasesGummadi, Tulasi; Zhang, Ben Y.; Valpione, Sara; Kim, Chul; Kottschade, Lisa A.; Mittapalli, Rajendar K.; Chiarion-Sileni, Vanna; Pigozzo, Jacopo; Elmquist, William F.; Dudek, Arkadiusz Z.Melanoma Research (2015), 25 (1), 75-79CODEN: MREEEH; ISSN:0960-8931. (Lippincott Williams & Wilkins)The impact of BRAF mutations in metastatic melanoma on the incidence of brain metastases and melanoma prognosis and the effect of BRAF inhibitors on the incidence of brain metastases has not been defined. Therefore, a retrospective anal. of patients with metastatic melanoma treated at three institutions was carried out to examine the impact of BRAF mutations and a BRAF inhibitor, vemurafenib, on the incidence of brain metastases. A retrospective review of 436 records revealed no difference in the incidence of brain metastases between patients with BRAF-mutated tumors vs. those without (incidence rate ratio=1.11, 95% confidence interval: 0.80-1.53; P=0.53). A lower incidence of brain metastases was obsd. in patients with BRAF-mutated tumors who took vemurafenib before the development of brain metastases vs. those who did not (incidence rate ratio=0.51, 95% confidence interval: 0.30-0.86; P=0.009). Although treatment with vemurafenib led to improvement in extracranial disease control, it did not significantly affect progression of existing intracranial disease and survival in these patients (P=0.7). Although our previous preclin. data have indicated that penetration of vemurafenib into the brain is limited, our retrospective anal. showed that there was a lower incidence of brain metastases in patients with BRAF-mutated tumors who took vemurafenib before the diagnosis of brain metastases.(c) Dummer, R.; Goldinger, S. M.; Turtschi, C. P.; Eggmann, N. B.; Michielin, O.; Mitchell, L.; Veronese, L.; Hilfikeer, P. R.; Felderer, L.; Rinderknecht, J. D. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study Eur. J. Cancer 2014, 50, 611– 621 DOI: 10.1016/j.ejca.2013.11.002(d) Robinson, G. W.; Orr, B. A.; Gajjar, A. Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multi-forme after BRAF Inhibitor therapy BMC Cancer 2014, 14, 258 DOI: 10.1186/1471-2407-14-258
- 223(a) Falchook, G. S.; Long, G. V.; Kurzrock, R.; Kim, K. B.; Arkenau, T. H.; Brown, M. P.; Hamid, O.; Infante, J. R.; Millward, M.; Pavlick, A. C.; O’Day, S. J.; Blackman, S. C.; Curtis, C. M.; Lebowitz, P.; Ma, B.; Ouellet, D.; Kefford, R. F. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase I dose-escalation trial Lancet 2012, 379, 1893– 1901 DOI: 10.1016/S0140-6736(12)60398-5(b) Long, G. V.; Trefzer, U.; Davies, M. A.; Kefford, R. F.; Ascierto, P. A.; Chapman, P. B.; Puzanov, I.; Hauschild, A.; Robert, C.; Algazi, A.; Mortier, L.; Tawbi, H.; Wilhelm, T.; Zimmer, L.; Switzky, J.; Swann, S.; Martin, A. M.; Guckert, M.; Goodman, V.; Streit, M.; Kirkwood, J. M.; Schadendorf, D. Dabrafenib in patients with Val600Glu or V600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicenter, open-label, phase 2 trial Lancet Oncol. 2012, 13, 1087– 1095 DOI: 10.1016/S1470-2045(12)70431-X[Crossref], [PubMed], [CAS], Google Scholar223bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1WqurzP&md5=dacdaec26bdcb06f1ed07b682c812785Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trialLong, Georgina V.; Trefzer, Uwe; Davies, Michael A.; Kefford, Richard F.; Ascierto, Paolo A.; Chapman, Paul B.; Puzanov, Igor; Hauschild, Axel; Robert, Caroline; Algazi, Alain; Mortier, Laurent; Tawbi, Hussein; Wilhelm, Tabea; Zimmer, Lisa; Switzky, Julie; Swann, Suzanne; Martin, Anne-Marie; Guckert, Mary; Goodman, Vicki; Streit, Michael; Kirkwood, John M.; Schadendorf, DirkLancet Oncology (2012), 13 (11), 1087-1095CODEN: LOANBN; ISSN:1470-2045. (Elsevier Ltd.)Background: Brain metastases are common in patients with metastatic melanoma and median overall survival from their diagnosis is typically 17-22 wk. We assessed dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain. Methods: We undertook a multicentre, open-label, phase 2 trial in 24 centers in six countries. We enrolled patients with histol. confirmed Val600Glu or Val600Lys BRAF-mutant melanoma and at least one asymptomatic brain metastasis (≥5 mm and ≤40 mm in diam.). Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncol. Group performance status of 0 or 1, and had adequate organ function. Patients were split into two cohorts: those in cohort A had not received previous local treatment for brain metastases and those in cohort B had progressive brain metastases after previous local treatments. Patients received 150 mg oral dabrafenib twice a day until disease progression, death, or unacceptable adverse events. The primary endpoint was the proportion of patients with Val600Glu BRAF-mutant melanoma who achieved an overall intracranial response, which was defined as a complete response or partial response assessed with a modified form of Response Evaluation Criteria in Solid Tumors (RECIST 1.1). We included patients who received at least one dose of dabrafenib in efficacy and safety analyses. This study is registered with ClinicalTrials.gov, no. NCT01266967. Findings: Between Feb 2, 2011, and Aug 5, 2011, we enrolled 172 patients: 89 (52%) in cohort A and 83 (48%) in cohort B. 139 (81%) had Val600Glu BRAF-mutant melanoma. 29 (39·2%, 95% CI 28·0-51·2) of 74 patients with Val600Glu BRAF-mutant melanoma in cohort A achieved an overall intracranial response, as did 20 (30·8%, 19·9-43·4) of 65 in cohort B. One (6·7%, 0·2-31·9) of 15 patients with Val600Lys BRAF-mutant melanoma achieved an overall intracranial response in cohort A, as did four (22·2%, 6·4-47·6) of 18 such patients in cohort B. Treatment-related adverse events of grade 3 or worse occurred in 38 (22%) patients. Eleven (6%) patients developed squamous-cell carcinoma (five [6%] patients in cohort A, of whom one also had keratoacanthoma; six [7%] in cohort B). Four grade 4 treatment-related adverse events occurred in cohort A: one blood amylase increase, one convulsion, one lipase increase, and one neutropenia. Two grade 4 events occurred in cohort B: one agranulocytosis and one intracranial hemorrhage. 51 (30%) patients had a serious adverse event. The three most frequent serious adverse events were pyrexia (ten [6%] patients), intracranial hemorrhage (ten [6%]; one treatment-related), and squamous-cell carcinoma (11 [6%]). Interpretation: Dabrafenib has activity and an acceptable safety profile in patients with Val600Glu BRAF-mutant melanoma and brain metastases irresp. of whether they are untreated or have been previously treated but have progressed. Funding: GlaxoSmithKline.
- 224Vaidhyanathan, S.; Mittapalli, R. K.; Sarkaria, J. N.; Elmquist, W. F. Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases Drug Metab. Dispos. 2014, 42, 1292– 1300 DOI: 10.1124/dmd.114.058339
- 225(a) Mittapalli, R. K.; Vaidhyanathan, S.; Sane, R.; Elmquist, W. F. Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032) J. Pharmacol. Exp. Ther. 2012, 342, 33– 40 DOI: 10.1124/jpet.112.192195[Crossref], [PubMed], [CAS], Google Scholar225ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVOktbjE&md5=68483daffd06025efca561991a4ae0f1Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032)Mittapalli, Rajendar K.; Vaidhyanathan, Shruthi; Sane, Ramola; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2012), 342 (1), 33-40CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Vemurafenib [N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide(PLX4032)] is a novel small-mol. BRAF inhibitor, recently approved by the Food and Drug Administration for the treatment of patients with metastatic melanoma with a BRAFV600E mutation. The objective of this study was to investigate the role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in the distribution of vemurafenib to the central nervous system. In vitro studies conducted in transfected Madin-Darby canine kidney II cells show that the intracellular accumulation of vemurafenib is significantly restricted because of active efflux by P-gp and BCRP. Bidirectional flux studies indicated greater transport in the basolateral-to-apical direction than the apical-to-basolateral direction because of active efflux by P-gp and BCRP. The selective P-gp and BCRP inhibitors zosuquidar and (3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino(1',2':1,6)pyrido(3,4-b)indole-3-propanoic acid-1,1-dimethylethyl ester (Ko143) were able to restore the intracellular accumulation and bidirectional net flux of vemurafenib. The in vivo studies revealed that the brain distribution coeff. (area under the concn. time profile of brain/area under the concn. time profile of plasma) of vemurafenib was 0.004 in wild-type mice. The steady-state brain-to-plasma ratio of vemurafenib was 0.035 ± 0.009 in Mdr1a/b(-/-) mice, 0.009 ± 0.006 in Bcrp1(-/-) mice, and 1.00 ± 0.19 in Mdr1a/b(-/-)Bcrp1(-/-) mice compared with 0.012 ± 0.004 in wild-type mice. These data indicate that the brain distribution of vemurafenib is severely restricted at the blood-brain barrier because of active efflux by both P-gp and BCRP. This finding has important clin. significance given the ongoing trials examg. the efficacy of vemurafenib in brain metastases of melanoma.(b) Mittapalli, R. K.; Vaidhyanathan, S.; Dudek, A. Z.; Elmquist, W. F. Mechanisms limiting distribution of the threonine-protein kinase B-RafV600E inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases J. Pharmacol. Exp. Ther. 2013, 344, 655– 664 DOI: 10.1124/jpet.112.201475[Crossref], [PubMed], [CAS], Google Scholar225bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjvVaju7Y%253D&md5=a1017480b1ec89e0942480fe60c7f4a8Mechanisms limiting distribution of the threonine-protein kinase B-RaFV600E inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastasesMittapalli, Rajendar K.; Vaidhyanathan, Shruthi; Dudek, Arkadiusz Z.; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2013), 344 (3), 655-664CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Brain metastases are a common cause of death in stage IV metastatic melanoma. Dabrafenib is a BRAF (gene encoding serine/threonine-protein kinase B-Raf) inhibitor that has been developed to selectively target the valine 600 to glutamic acid substitution (BRAFV600E), which is commonly found in metastatic melanoma. Clin. trials with dabrafenib have shown encouraging results; however, the central nervous system distribution of dabrafenib remains unknown. Thus, the objective of the current study was to evaluate the brain distribution of dabrafenib in mice, and to see whether active efflux by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restricts its delivery across the blood-brain barrier (BBB). In vitro accumulation studies conducted in Madin-Darby canine kidney II cells indicate that dabrafenib is an avid substrate for both P-gp and BCRP. Directional flux studies revealed greater transport in the basolateral to apical direction with cor. efflux ratios greater than 2 for both P-gp and Bcrp1 transfected cell lines. In vivo, the ratio of area under the concn.-time curve (AUC)brain to AUCplasma (Kp) of dabrafenib after an i.v. dose (2.5 mg/kg) was 0.023, which increased by 18-fold in Mdr1 a/b-/-Bcrp1-/- mice to 0.42. Dabrafenib plasma exposure was ∼2-fold greater in Mdr1 a/b-/-Bcrp1-/- mice as compared with wild-type with an oral dose (25 mg/kg); however, the brain distribution was increased by ∼10-fold with a resulting Kp of 0.25. Further, compared with vemurafenib, another BRAFV600E inhibitor, dabrafenib showed greater brain penetration with a similar dose. In conclusion, the dabrafenib brain distribution is limited in an intact BBB model, and the data presented herein may have clin. implications in the prevention and treatment of melanoma brain metastases.
- 226Williams, T. E.; Subramanian, S.; Verhagen, J.; McBride, C. M.; Costales, A.; Sung, L.; Antonios-McCrea, W.; McKenna, M.; Louie, A. K.; Ramurthy, S.; Levine, B.; Shafer, C. M.; Machajewski, T.; Renhowe, P. A.; Appleton, B. A.; Amiri, P.; Chou, J.; Stuart, D.; Aardalen, K.; Poon, D. Discovery of RAF265: a potent mut-B-Raf inhibitor for the treatment of metastatic melanoma ACS Med. Chem. Lett. 2015, 6, 961– 965 DOI: 10.1021/ml500526p[ACS Full Text], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Kms7jO&md5=d8292ddc806a7a1b352f34abc232d84dDiscovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic MelanomaWilliams, Teresa E.; Subramanian, Sharadha; Verhagen, Joelle; McBride, Christopher M.; Costales, Abran; Sung, Leonard; Antonios-McCrea, William; McKenna, Maureen; Louie, Alicia K.; Ramurthy, Savithri; Levine, Barry; Shafer, Cynthia M.; Machajewski, Timothy; Renhowe, Paul A.; Appleton, Brent A.; Amiri, Payman; Chou, James; Stuart, Darrin; Aardalen, Kimberly; Poon, DanielACS Medicinal Chemistry Letters (2015), 6 (9), 961-965CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clin. trials.
- 227Liu, X.; Ide, J. L.; Norton, I.; Marchionni, M. A.; Ebling, M. C.; Wang, L. Y.; Davis, E.; Sauvageot, C. M.; Kesari, S.; Kellersberger, K. A.; Easterling, M. L.; Santagata, S.; Stuart, D. D.; Alberta, J.; Agar, J. N.; Stiles, C. D.; Agar, N. Y. R. Molecular imaging of drug transit through the blood-brain barrier with MALDI mass spectrometry imaging Sci. Rep. 2013, 3, 2859 DOI: 10.1038/srep02859[Crossref], [PubMed], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c%252FlvFCiug%253D%253D&md5=a496de9b3b29c80f27b8174d9da8e715Molecular imaging of drug transit through the blood-brain barrier with MALDI mass spectrometry imagingLiu Xiaohui; Ide Jennifer L; Norton Isaiah; Marchionni Mark A; Ebling Maritza C; Wang Lan Y; Davis Erin; Sauvageot Claire M; Kesari Santosh; Kellersberger Katherine A; Easterling Michael L; Santagata Sandro; Stuart Darrin D; Alberta John; Agar Jeffrey N; Stiles Charles D; Agar Nathalie Y RScientific reports (2013), 3 (), 2859 ISSN:.Drug transit through the blood-brain barrier (BBB) is essential for therapeutic responses in malignant glioma. Conventional methods for assessment of BBB penetrance require synthesis of isotopically labeled drug derivatives. Here, we report a new methodology using matrix assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) to visualize drug penetration in brain tissue without molecular labeling. In studies summarized here, we first validate heme as a simple and robust MALDI MSI marker for the lumen of blood vessels in the brain. We go on to provide three examples of how MALDI MSI can provide chemical and biological insights into BBB penetrance and metabolism of small molecule signal transduction inhibitors in the brain - insights that would be difficult or impossible to extract by use of radiolabeled compounds.
- 228Liveblogging First-Time Disclosures of Drug Structures from #ACSNOLA. http://cenblog.org/the-haystack/2013/04/liveblogging-first-time-disclosures-of-drug-structures-from-acsnola/ (ccessed June 10, 2016) .
- 229Rusconi, P.; Caiola, E.; Broggini, M. Ras/Raf/MEK inhibitors in oncology Curr. Med. Chem. 2012, 19, 1164– 1176 DOI: 10.2174/092986712799320510[Crossref], [PubMed], [CAS], Google Scholar229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1Kktro%253D&md5=8f035e72d81b5703de0e5782102726e9RAS/RAF/MEK inhibitors in oncologyRusconi, P.; Caiola, E.; Broggini, M.Current Medicinal Chemistry (2012), 19 (8), 1164-1176CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. The RAS/RAF/MEK signaling pathway plays a central role in mediating both proliferation and survival of cancer cells. These proteins are a group of serine/threonine kinases activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface towards both nuclear and cytosolic targets. In combination with several other signaling pathways, they can differentially alter phosphorylation status of the transcription factors. A controlled regulation of these cascades is involved in cell proliferation and differentiation, whereas an unregulated activation of these kinases can result in oncogenesis. Dysregulation of the RAS/RAF/MEK pathway was detected in > 30% of human tumors, however mutations in the MEK1 and MEK2 genes are seldom, so that hyperactivation of MEK1/2 usually results from gain-of-function mutations in RAS and/or B-RAF. In addn., alteration of the pathways is often assocd. with drug resistance in the clinic, such as the case of K-RAS mutant expressing tumors. Since RAS protein is a difficult target, alternative ways altering post-translational modifications using farnesyl transferase inhibitors were adopted. Drug discovery programs have therefore largely focused on B-RAF and MEK. In this review we will discuss the most promising strategies developed to target these kinases and the most recent inhibitors facing the preclin. and clin. setting, also considering their structure-activity relationship (SAR).
- 230Choo, E. F.; Ly, J.; Chan, J.; Shahidi-Latham, S. K.; Messick, K.; Plise, E.; Quiason, C. M.; Yang, L. Role of P-glycoprotein on the brain penetration and brain pharmacodynamic activity of the MEK inhibitor cobimetinib Mol. Pharmaceutics 2014, 11, 4199– 4207 DOI: 10.1021/mp500435s[ACS Full Text], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFygtLbO&md5=90fef69297bcd8db6878894b65949b13Role of P-Glycoprotein on the Brain Penetration and Brain Pharmacodynamic Activity of the MEK Inhibitor CobimetinibChoo, Edna F.; Ly, Justin; Chan, Jocelyn; Shahidi-Latham, Sheerin K.; Messick, Kirsten; Plise, Emile; Quiason, Cristine M.; Yang, LuluMolecular Pharmaceutics (2014), 11 (11), 4199-4207CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Cobimetinib is a MEK inhibitor currently in clin. trials as an anticancer agent. The objectives of this study were to det. in vitro and in vivo if cobimetinib is a substrate of P-glycoprotein (P-gp) and/or breast cancer resistance protein (Bcrp1) and to assess the implications of efflux on cobimetinib pharmacokinetics (PK), brain penetration, and target modulation. Cell lines transfected with P-gp or Bcrp1 established that cobimetinib was a substrate of P-gp but not a substrate of Bcrp1. In vivo, after i.v. and oral administration of cobimetinib to FVB (wild-type; WT), Mdr1a/b(-/-), Bcrp1 (-/-), and Mdr1a/b(-/-)/Bcrp(-/-) knockout (KO) mice, clearance was similar in WT (35.5 ± 16.7 mL/min/kg) and KO animals (22.0 ± 3.6 to 27.6 ± 5.2 mL/min/kg); oral exposure was also similar between WT and KO animals. After an oral 10 mg/kg dose of cobimetinib, the mean total brain to plasma ratio (Kp) at 6 h postdose was 0.3 and 0.2 in WT and Bcrp1(-/-) mice, resp. In Mdr1a/b(-/-) and Mdr1a/1b/Bcrp1(-/-) KO mice and WT mice treated with elacridar (a P-gp and BCRP inhibitor), Kp increased to 11, 6, and 7, resp. Increased brain exposure in Mdr1a/b(-/-) and Mdr1a/1b/Bcrp1(-/-) KO and elacridar treated mice was accompanied by up to ∼65% suppression of the target (pErk) in brain tissue, compared to WT mice. By MALDI imaging, the cobimetinib signal intensity was relatively high and was dispersed throughout the brain of Mdr1a/1b/Bcrp1(-/-) KO mice compared to low/undetectable signal intensity in WT mice. The efflux of cobimetinib by P-gp may have implications for the treatment of patients with brain tumors/metastases.
- 231(a) Choo, E. F.; Belvin, M.; Boggs, J.; Deng, Y.; Hoeflich, K. P.; Ly, J.; Merchant, M.; Orr, C.; Plise, E.; Robarge, K.; Martini, J. F.; Kassees, R.; Aoyama, R. G.; Ramaiya, A.; Johnston, S. H. Preclinical disposition of GDC-0973 and prospective and retrospective analysis of human dose and efficacy predictions Drug Metab. Dispos. 2012, 40, 919– 927 DOI: 10.1124/dmd.111.043778(b) Gilmartin, A. G.; Bleam, M. R.; Groy, A.; Moss, K. G.; Minthorn, E. A.; Kulkami, S. G.; Rominger, C. M.; Erskine, S.; Fisher, K. E.; Yang, J.; Azppacosta, F.; Annan, R.; Sutton, D.; Laquerre, S. G. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition Clin. Cancer Res. 2011, 17, 989– 1000 DOI: 10.1158/1078-0432.CCR-10-2200[Crossref], [PubMed], [CAS], Google Scholar231bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXis1eit7k%253D&md5=6154be5fa0afb034c6a5995508d7ea9eGSK1120212 (JTP-74057) Is an Inhibitor of MEK Activity and Activation with Favorable Pharmacokinetic Properties for Sustained In Vivo Pathway InhibitionGilmartin, Aidan G.; Bleam, Maureen R.; Groy, Arthur; Moss, Katherine G.; Minthorn, Elisabeth A.; Kulkarni, Swarupa G.; Rominger, Cynthia M.; Erskine, Symon; Fisher, Kelly E.; Yang, Jing-Song; Zappacosta, Francesca; Annan, Roland; Sutton, David; Laquerre, Sylvie G.Clinical Cancer Research (2011), 17 (5), 989-1000CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: Despite their preclin. promise, previous MEK inhibitors have shown little benefit for patients. This likely reflects the narrow therapeutic window for MEK inhibitors due to the essential role of the P42/44 MAPK pathway in many nontumor tissues. GSK1120212 is a potent and selective allosteric inhibitor of the MEK1 and MEK2 (MEK1/2) enzymes with promising antitumor activity in a phase I clin. trial (ASCO 2010). Our studies characterize GSK1120212' enzymic, cellular, and in vivo activities, describing its unusually long circulating half-life. Exptl. Design: Enzymic studies were conducted to det. GSK1120212 inhibition of recombinant MEK, following or preceding RAF kinase activation. Cellular studies examd. GSK1120212 inhibition of ERK1 and 2 phosphorylation (p-ERK1/2) as well as MEK1/2 phosphorylation and activation. Further studies explored the sensitivity of cancer cell lines, and drug pharmacokinetics and efficacy in multiple tumor xenograft models. Results: In enzymic and cellular studies, GSK1120212 inhibits MEK1/2 kinase activity and prevents Raf-dependent MEK phosphorylation (S217 for MEK1), producing prolonged p-ERK1/2 inhibition. Potent cell growth inhibition was evident in most tumor lines with mutant BRAF or Ras. In xenografted tumor models, GSK1120212 orally dosed once daily had a long circulating half-life and sustained suppression of p-ERK1/2 for more than 24 h; GSK1120212 also reduced tumor Ki67, increased p27Kip1/CDKN1B, and caused tumor growth inhibition in multiple tumor models. The largest antitumor effect was among tumors harboring mutant BRAF or Ras. Conclusions: GSK1120212 combines high potency, selectivity, and long circulating half-life, offering promise for successfully targeting the narrow therapeutic window anticipated for clin. MEK inhibitors.
- 232(a) Widemann, B. C.; Marcus, L. J.; Fisher, M. J.; Weiss, B. D.; Kim, A.; Dombi, E.; Baldwin, A.; Whitcomb, P.; Martin, S.; Gillespie, A.; Doyle, A. Phase I study of the MEK1/2 inhibitor selumetinib (AZ6244) hydrogen sulfate in children and young adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs) J. Clin. Oncol. 2014, 32 (Suppl.) 10018(b) https://clinicaltrials.gov/ct2/show/NCT01089101 (accessed June 12, 2016) .
- 233Binimetinib has advanced to a trial enrolling patients with brain cancer: https://clinicaltrials.gov/ct2/show/NCT02285439 (accessed June 10, 2016) .
- 234Iverson, C.; Larson, G.; Lai, C.; Yeh, L. T.; Dadson, C.; Weingarten, P.; Appleby, T.; Vo, T.; Maderna, A.; Vernier, J. M.; Hamatake, R.; Miner, J. N.; Quart, B. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer Cancer Res. 2009, 69, 6839– 6847 DOI: 10.1158/0008-5472.CAN-09-0679[Crossref], [PubMed], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVOmt7fF&md5=f12a941d012d72bb0efc8c4453dedd85RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of CancerIverson, Cory; Larson, Gary; Lai, Chon; Yeh, Li-Tain; Dadson, Claudia; Weingarten, Paul; Appleby, Todd; Vo, Todd; Maderna, Andreas; Vernier, Jean-Michel; Hamatake, Robert; Miner, Jeffrey N.; Quart, BarryCancer Research (2009), 69 (17), 6839-6847CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway provides numerous opportunities for targeted oncol. therapeutics. In particular, the MEK enzyme is attractive due to high selectivity for its target ERK and the central role that activated ERK plays in driving cell proliferation. The structural, pharmacol., and pharmacokinetic properties of RDEA119/BAY 869766, an allosteric MEK inhibitor, are presented. RDEA119/BAY 869766 is selectively bound directly to an allosteric pocket in the MEK1/2 enzymes. This compd. is highly efficacious at inhibiting cell proliferation in several tumor cell lines in vitro. In vivo, RDEA119/BAY 869766 exhibits potent activity in xenograft models of melanoma, colon, and epidermal carcinoma. RDEA119/BAY 869766 exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice. RDEA119/BAY 869766 shows a tissue selectivity that reduces its potential for central nervous system-related side effects. Using pharmacokinetic and pharmacodynamic data, we show that maintaining adequate MEK inhibition throughout the dosing interval is likely more important than achieving high peak levels because greater efficacy was achieved with more frequent but lower dosing. Based on its longer half-life in humans than in mice, RDEA119/BAY 869766 has the potential for use as a once- or twice-daily oral treatment for cancer. RDEA119/BAY 869766, an exquisitely selective, orally available MEK inhibitor, has been selected for clin. development because of its potency and favorable pharmacokinetic profile.
- 235Isshiki, Y.; Kohchi, Y.; Iikura, H.; Matsubara, Y.; Asoh, K.; Murata, T.; Kohchi, M.; Mizuguchi, E.; Tsujii, S.; Hattori, K.; Miura, T.; Yoshimura, Y.; Aida, S.; Miwa, M.; Saitoh, R.; Murao, N.; Okabe, H.; Belunis, C.; Janson, C.; Lukacs, C.; Schuck, V.; Shimma, N. Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent Bioorg. Med. Chem. Lett. 2011, 21, 1795– 1801 DOI: 10.1016/j.bmcl.2011.01.062
- 236Cohen, R. B.; Aamdal, S.; Nyakas, M.; Cavallin, M.; Green, D.; Learoyd, M.; Smith, I.; Kurzrock, R. A phase I dose-finding, safety and tolerability study of AZD8330 in patients with advanced malignancies Eur. J. Cancer 2013, 49, 1521– 1529 DOI: 10.1016/j.ejca.2013.01.013
- 237Shaw, J. V.; Zhang, H.; Carden, R.; Qiu, D.; Tian, H.; Ma, J.; Clark, A.; Ogden, J.; Goodstal, S. Abstract LB-456: Evaluation of brain pharmacokinetics as a potential differentiation factor for the MEK inhibitors, MSC2015103 and pimasertib Cancer Res. 2012, 72, LB-456 DOI: 10.1158/1538-7445.AM2012-LB-456
- 238Goutopoulos, A.; Askew, B.; Bankston, D.; Clark, A.; Dhanabal, M.; Dong, R.; Fischer, D.; Healey, B.; Jiang, X.; Josephson, K.; Lin, J.; Ma, J.; Noonan, T.; Qiu, D.; Rocha, C.; Romanelli, A.; Shutes, A.; Spooner, E.; Tian, H.; Yu, H. Abstract 4476: AS703026: a novel allosteric MEK inhibitor Cancer Res. 2009, 69 (Suppl.) 4776
- 239Shen, Y.; Boivin, R.; Yoneda, N.; Du, H.; Schiller, S.; Matsushima, T.; Goto, M.; Shirota, H.; Gusovsky, F.; Lemelin, C.; Jiang, Y.; Zhang, Z.; Pelletier, R.; Ikemori-Kawada, M.; Kawakami, Y.; Inoue, A. Discovery of anti-inflammatory clinical candidate E6201, inspired from resorcylic lactone LL-Z1640-2, III Bioorg. Med. Chem. Lett. 2010, 20, 3155– 3157 DOI: 10.1016/j.bmcl.2010.03.087
- 240Wu, J.; Nomoto, K.; Wang, J.; Kuznetsov, G.; Agoulnik, S.; Shuck, E.; Wong, N.; Towle, M.; Schnaderbeck, M.; Wu, S.; Littlefield, B. Abstract 3687: In vivo anticancer activity of E6201, a novel MEK1 inhibitor, against BRAF-mutated human cancer xenografts Cancer Res. 2009, 69 (Suppl.) 3687
- 241(a) Lee, C.; Fotovati, A.; Triscott, J.; Chen, J.; Venugopal, C.; Singhal, A.; Dunham, C.; Kerr, J. M.; Verreault, M.; Yip, S.; Wakimoto, H.; Jones, C.; Jayanthan, A.; Narendran, A.; Singh, S. K.; Dunn, S. E. Polo-like kinase 1 inhibition kills glioblastoma multiforme brain tumor cells in part through loss of SOX2 and delays tumor progression in mice Stem Cells 2012, 30, 1064– 1075 DOI: 10.1002/stem.1081(b) Danovi, D.; Folarin, A.; Gogolok, S.; Ender, C.; Elbatsh, A. M. O.; Engström, P. G.; Stricker, S. H.; Gagrica, S.; Georgian, A.; Yu, D.; U, K. P.; Harvey, K. J.; Ferretti, P.; Paddison, P. J.; Preston, J. E.; Abbott, N. J.; Bertone, P.; Smith, A.; Pollard, S. M. A high-content small molecule screen identifies sensitivity of glioblastoma stem cells to inhibition of polo-like kinase 1 PLoS One 2013, 8, e77053 DOI: 10.1371/journal.pone.0077053(c) Pezuk, J. A.; Brassesco, M. S.; Morales, A. G.; de Oliveira, J. C.; de Paula Queiroz, R. G.; Machado, H. R.; Carlotti, C. G.; Neder, L.; Scrideli, C. A.; Tone, L. G. Polo-like kinase 1 inhibition causes decreased proliferation by cell cycle arrest, leading to cell death in glioblastoma Cancer Gene Ther. 2013, 20, 499– 506 DOI: 10.1038/cgt.2013.46[Crossref], [PubMed], [CAS], Google Scholar241chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFKnu7jI&md5=bb21c197c08f06df5bf1bf0e8d28f187Polo-like kinase 1 inhibition causes decreased proliferation by cell cycle arrest, leading to cell death in glioblastomaPezuk, J. A.; Brassesco, M. S.; Morales, A. G.; de Oliveira, J. C.; de Paula Queiroz, R. G.; Machado, H. R.; Carlotti, C. G. Jr; Neder, L.; Scrideli, C. A.; Tone, L. G.Cancer Gene Therapy (2013), 20 (9), 499-506CODEN: CGTHEG; ISSN:0929-1903. (Nature Publishing Group)Glioblastoma (GBM) is one of the most aggressive central nervous system tumors with a patient's median survival of <1 yr. Polo-like kinases (PLKs) are a family of serine/threonine kinases that have key roles in cell cycle control and DNA-damage response. We evaluated PLK1, 2, 3 and 4 gene expression in 8 GBM cell lines and 17 tumor samples, and analyzed the effect of the PLK1 inhibition on SF188 and T98G GBM cell lines and 13 primary cultures. Our data showed PLK1 overexpression and a variable altered expression of PLK2, 3 and 4 genes in GBM tumor samples and cell lines. Treatments with nanomolar concns. of BI 2536, BI 6727, GW843682X or GSK461364 caused a significant decrease in GBM cells proliferation. Colony formation was also found to be inhibited (P<0.05), whereas apoptosis rate and mitotic index were significantly increased (P<0.05) after PLK1 inhibition in both GBM cell lines. Cell cycle anal. showed an arrest at G2 (P<0.05) and cell invasion was also decreased after PLK1 inhibition. Furthermore, simultaneous combinations of BI 2536 and temozolomide produced synergistic effects for both the cell lines after 48 h of treatment. Our findings suggest that PLK1 might be a promising target for the treatment of GBMs.(d) Tandle, A. T.; Kramp, T.; Kil, W. J.; Halthore, A.; Gehlhaus, K.; Shankavaram, U.; Tofilon, P. J.; Caplen, N. J.; Camphausen, K. Inhibition of polo-like kinase 1 in glioblastoma multiforme induces mitotic catastrophe and enhances radiosensitisation Eur. J. Cancer 2013, 49, 3020– 3028 DOI: 10.1016/j.ejca.2013.05.013(e) Pezuk, J. A.; Brassesco, M. S.; Morales, A. G.; de Oliveira, J. C.; de Oliveira, H. F.; Scrideli, C. A.; Tone, L. G. Inhibition of polo-like kinase 1 induces cell cycle arrest and sensitizes glioblastoma cells to ionizing radiation Cancer Biother.Radiopharm. 2013, 28, 516– 522 DOI: 10.1089/cbr.2012.1415[Crossref], [PubMed], [CAS], Google Scholar241ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Kht7jF&md5=64b00b16718879217b959eab70abdcd9Inhibition of Polo-Like Kinase 1 Induces Cell Cycle Arrest and Sensitizes Glioblastoma Cells to Ionizing RadiationPezuk, Julia Alejandra; Brassesco, Maria Sol; Morales, Andressa Gois; Carvalho de Oliveira, Jaqueline; Francisco de Oliveira, Harley; Scrideli, Carlos Alberto; Tone, Luiz GonzagaCancer Biotherapy and Radiopharmaceuticals (2013), 28 (7), 516-522CODEN: CBRAFJ; ISSN:1084-9785. (Mary Ann Liebert, Inc.)Despite efforts to improve surgical, radiol., and chemotherapeutic strategies, the outcome of patients with glioblastoma (GBM) is still poor. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays key roles in cell cycle control and has been assocd. with tumor growth and prognosis. Here, we aimed at testing the radiosensitizing effects of the PLK1 inhibitor BI 2536 on eight GBM cell lines. For cell cycle anal., T98G, U251, U343 MG-a, LN319, SF188, U138 MG, and U87 MG cell lines were treated with 10, 50, or 100 nM of BI 2536 for 24 h. In addn., cell cultures exposed to BI 2536 50 nM for 24 h were irradiated with γ-rays from 60Cobalt source at final doses of 2, 4, and 6 Gy. Combinatorial effects were evaluated through proliferation and clonogenic capacity assays. Treatment with BI 2536 caused mitotic arrest after 24 h, and increased apoptosis in GBM cells. Moreover, our results demonstrate that pretreatment with this drug sensitized six out of seven GBM cell lines to different doses of γ-irradn. as shown by decreased growth and abrogation of colony-formation capacity. Our data suggest that PLK1 blockage has a radiosensitizing effect on GBM, which could improve treatment strategies for this devastating tumor.(f) Triscott, J.; Lee, C.; Foster, C.; Manoranjan, B.; Pamid, M. R.; Berns, R.; Fotovati, A.; Venugopal, C.; O’Halloran, K.; Narendran, A.; Hawkins, C.; Ramaswamy, V.; Bouffet, E.; Taylor, M. D.; Singhal, A.; Hukin, J.; Rassekh, R.; Yip, S.; Northcott, P.; Singh, S. K.; Dunham, C.; Dunn, S. Personalizing the treatment of pediatric medulloblastoma: polo-like kinase 1 as a molecular target in high-risk children Cancer Res. 2013, 73, 6734– 6744 DOI: 10.1158/0008-5472.CAN-12-4331
- 242(a) Markant, S. L.; Esparza, L. A.; Sun, J.; Barton, K. L.; McCoig, L. M.; Grant, G. A.; Crawford, J. R.; Levy, M. L.; Northcott, P. A.; Shih, D.; Remke, M.; Taylor, M. D.; Wechsler-Reya, R. J. Targeting sonic hedgehog-associated medulloblastoma through inhibition of aurora and polo-like kinases Cancer Res. 2013, 73, 6310– 6322 DOI: 10.1158/0008-5472.CAN-12-4258(b) Barton, V. N.; Foreman, N. K.; Donson, A. M.; Birks, D. K.; Handler, M. H.; Vibhakar, R. Aurora kinase A as a rational target for therapy in glioblastoma J. Neurosurg. Pediatr. 2010, 6, 98– 105 DOI: 10.3171/2010.3.PEDS10120[Crossref], [PubMed], [CAS], Google Scholar242bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cnktlagsw%253D%253D&md5=58271fedc8396c9e1a856991991b30e2Aurora kinase A as a rational target for therapy in glioblastomaBarton Valerie N; Foreman Nicholas K; Donson Andrew M; Birks Diane K; Handler Michael H; Vibhakar RajeevJournal of neurosurgery. Pediatrics (2010), 6 (1), 98-105 ISSN:.OBJECT: Despite advances in the knowledge of tumor biology, the outcome of glioblastoma tumors remains poor. The design of many molecularly targeted therapies in glioblastoma has focused on inhibiting molecular abnormalities present in tumor cells compared with normal tissue rather than patient outcome-associated factors. As an alternative approach, the present study identified genes associated with shorter survival as potential therapeutic targets. It was hypothesized that inhibition of a molecular target associated with poor outcome would impact glioblastoma cell proliferation. METHODS: The present study correlated patient survival data with tumor gene expression profiling and gene ontology analysis. Genes associated with shorter survival were identified and one of these was selected for therapeutic targeting in an in vitro system. Glioblastoma cell growth suppression was measured by H(3)-thymidine uptake, colony formation, and flow cytometry. RESULTS: The gene expression microarray and ontology analysis revealed that genes involved in mitotic processes, including AURKA, were associated with poor prognosis in glioblastoma. Inhibition of AURKA suppressed glioblastoma cell growth. Moreover, inhibition of AURKA was synergistic with radiation in glioblastoma cells at high radiation doses. CONCLUSIONS: Relative expression of AURKA may be of prognostic value and warrants further investigation with larger, prospective studies. Pharmacological inhibition of AURKA is a potentially promising therapy for glioblastoma.(c) Klein, A.; Reichardt, W.; Jung, V.; Zang, K. D.; Meese, E.; Urbschat, S. Overexpression and amplification of STK15 in human gliomas Int. J. Oncol. 2004, 25, 1789– 1794 DOI: 10.3892/ijo.25.6.1789[Crossref], [PubMed], [CAS], Google Scholar242chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhsVyjsw%253D%253D&md5=c7541c7f1d229f6794d3278dedb828cbOverexpression and amplification of STK15 in human gliomasKlein, Alexandra; Reichardt, Wilfried; Jung, Volker; Zang, Klaus D.; Meese, Eckart; Urbschat, SteffiInternational Journal of Oncology (2004), 25 (6), 1789-1794CODEN: IJONES; ISSN:1019-6439. (International Journal of Oncology)The serine/threonine kinase 15 (STK15) at chromosome 20q13.2 is frequently shown to be amplified and overexpressed in several human cancers. STK15 was reported to act as a cell cycle regulator and its overexpression induces centrosome amplification and aneuploidy. Recently the authors showed that STK15 even plays a role in human malignant brain tumors and the authors described an amplification of the gene in 31% of the investigated gliomas. In this study the authors scrutinized the correlation of increased STK15 on DNA and mRNA levels in gliomas of different histol. grades. Southern blotting confirmed the amplification frequency of the STK15 gene, which had been previously detected by comparative PCR. In total, DNA gains were found in 26% of the investigated gliomas. Interestingly, the authors detected overexpression of STK15 mRNA in 60% of the analyzed brain tumors. The elevated expression does not strongly correlate with gains on DNA level, but all cases with an amplification of the STK15 gene display overexpression. Gains of the STK15 gene seem to occur irresp. of the histol. grades of the tumors, so that STK15 probably is not a progression assocd. factor. Amplification and overexpression of the kinase rather represent a primary alteration in human gliomas, which could play an important role as an early event in all glioma subtypes.
- 243Li, N.; Maly, D. J.; Chanthery, Y. H.; Sirkis, D. W.; Nakamura, J. L.; Berger, M. S.; James, C. D.; Shokat, K. M.; Weiss, W. A.; Persson, A. I. Radiotherapy followed by aurora kinase inhibition targets tumor-propagating cells in human glioblastoma Mol. Cancer Ther. 2015, 14, 419– 428 DOI: 10.1158/1535-7163.MCT-14-0526[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitlOjsbg%253D&md5=a4c7daceb8c770e4cfb64d5b1bbeba61Radiotherapy Followed by Aurora Kinase Inhibition Targets Tumor-Propagating Cells in Human GlioblastomaLi, Nan; Maly, Dustin J.; Chanthery, Yvan H.; Sirkis, Daniel W.; Nakamura, Jean L.; Berger, Mitchel S.; James, C. David; Shokat, Kevan M.; Weiss, William A.; Persson, Anders I.Molecular Cancer Therapeutics (2015), 14 (2), 419-428CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Glioblastoma (GBM) is the most common malignant primary brain tumor. Radiotherapy fails to eliminate subpopulations of stem-like tumor-propagating cells (TPC), resulting in tumor regrowth. To identify kinases that promote TPC self-renewal rather than increasing proliferation in human GBM cultures, we screened a library of 54 nonselective tool compds. and detd. their kinase inhibitor profiles in vitro. Most compds. inhibited aurora kinase (AURK) activity and blocked TPC self-renewal, while inducing GBM cell polynucleation and apoptosis. To prevent regrowth by TPCs, we used a priming dose of radiation followed by incubation with the pan-AURK inhibitor VX680 to block self-renewal and induce apoptosis in GBM cultures. In mice xenografted with human GBM cells, radiotherapy followed by VX680 treatment resulted in reduced tumor growth and increased survival relative to either monotherapy alone or VX680 treatment before radiation. Our results indicate that AURK inhibition, subsequent to radiation, may enhance the efficacy of radiotherapy by targeting radioresistant TPCs in human GBMs. Mol Cancer Ther; 14(2); 419-28. ©2014 AACR.
- 244Wu, C.-P.; Hsieh, C.-H.; Hsiao, S.-H.; Luo, S.-Y.; Su, C.-Y.; Li, Y.-Q.; Huang, Y.-H.; Huang, C.-W.; Hsu, S.-C. Human ATP-binding cassette transporter ABCB1 confers resistance to volasertib (BI6727), a selective inhibitor of polo-like kinase 1 Mol. Pharmaceutics 2015, 12, 3885– 3895 DOI: 10.1021/acs.molpharmaceut.5b00312[ACS Full Text], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFKiu7rI&md5=57e74ce734e224b5e5da848c87d8ea7cHuman ATP-Binding Cassette Transporter ABCB1 Confers Resistance to Volasertib (BI 6727), a Selective Inhibitor of Polo-like Kinase 1Wu, Chung-Pu; Hsieh, Chia-Hung; Hsiao, Sung-Han; Luo, Shi-Yu; Su, Ching-Ya; Li, Yan-Qing; Huang, Yang-Hui; Huang, Chiun-Wei; Hsu, Sheng-ChiehMolecular Pharmaceutics (2015), 12 (11), 3885-3895CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)The overexpression of the serine/threonine specific polo-like kinase 1 (Plk1) is assocd. with poor prognosis in many types of cancer. Consequently, Plk1 has emerged as a valid therapeutic target for anticancer drug design. Volasertib is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting cell cycle arrest at nanomolar concns. However, the risk of developing drug resistance, which is often assocd. with the overexpression of the ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein), can present a therapeutic challenge for volasertib and many other therapeutic drugs. Although volasertib is highly effective against the proliferation of numerous cancer cell lines, the authors found that the overexpression of ABCB1 in cancer cells leads to cellular resistance to volasertib and reduces the level of volasertib-stimulated G2/M cell cycle arrest and subsequent onset of apoptosis. Furthermore, the authors demonstrate that volasertib competitively inhibits the function of ABCB1 and stimulates the basal ATPase activity of ABCB1 in a concn.-dependent manner, which is consistent with substrate transport by ABCB1. More importantly, the authors discovered that the coadministration of an inhibitor or drug substrate of ABCB1 restored the anticancer activity of volasertib in ABCB1-overexpressing cancer cells. In conclusion, the results of the authors' study reveal that ABCB1 neg. affects the efficacy of volasertib and supports its combination with a modulator of ABCB1 to improve clin. responses.
- 245Wu, C.-P.; Hsiao, S.-H.; Sim, H.-M.; Luo, S.-Y.; Tuo, W.-C.; Cheng, H.-W.; Li, Y.-Q.; Huan, Y.-H.; Ambudkar, S. V. Human ABCB1 (P-glycoprotein) and ABCG2 mediate resistance to BI 2536, a potent and selective inhibitor of polo-like kinase 1 Biochem. Pharmacol. 2013, 86, 904– 913 DOI: 10.1016/j.bcp.2013.08.004
- 246Wu, C.-P.; Hsiao, S.-H.; Luo, S.-Y.; Tuo, W.-C.; Su, C.-Y.; Li, Y.-Q.; Huang, Y.-H.; Hsieh, C. H. Overexpression of human ABCB1 in cancer cells leads to reduced activity of GSK461364, a specific inhibitor of polo-like kinase 1 Mol. Pharmaceutics 2014, 11, 3727– 3736 DOI: 10.1021/mp500492r[ACS Full Text], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVykurrE&md5=91eda9381c54d0d848bb0867a4b7f167Overexpression of Human ABCB1 in Cancer Cells Leads to Reduced Activity of GSK461364, a Specific Inhibitor of Polo-like Kinase 1Wu, Chung-Pu; Hsiao, Sung-Han; Luo, Shi-Yu; Tuo, Wei-Cherng; Su, Ching-Ya; Li, Yan-Qing; Huang, Yang-Hui; Hsieh, Chia-HungMolecular Pharmaceutics (2014), 11 (10), 3727-3736CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Polo-like kinase 1 (Plk1) is a serine/threonine kinase involved in the regulation of mitosis and is overexpressed in many tumor types. Inhibition of Plk1 leads to cell cycle arrest, onset of apoptosis, and cell death, thus Plk1 has emerged as an important target for cancer treatment. GSK461364 is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting G2/M cell cycle arrest at low concns. However, as is the case for many therapeutic drugs, the risk of developing drug resistance to GSK461364 can present a therapeutic challenge to clinicians. Since the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 is one of the most common mechanisms of drug resistance, we aimed to investigate the effect of ABCB1 on the cellular efficacy of GSK461364. In this study, we obsd. a significantly reduced activity of GSK461364 in cells overexpressing human ABCB1. We showed that GSK461364 stimulates the ABCB1 ATPase activity and competitively inhibits ABCB1-mediated efflux of calcein-AM in a concn.-dependent manner. Moreover, as a way to assess the impact of ABCB1 on the efficacy of GSK461364, we evaluated the G2/M cell cycle arrest and apoptosis induced by GSK461364. We discovered that, by inhibiting the function of ABCB1, the reduced G2/M cell cycle arrest, apoptosis, and sensitivity to GSK461364 treatment in ABCB1-overexpressing cells can be significantly restored. In conclusion, in order to achieve a better therapeutic outcome, combination therapy of GSK461364 with a modulator of ABCB1 should be further investigated as a potential treatment approach.
- 247White, M. P.; Babayeva, M.; Taft, D. R.; Maniar, M. Determination of intestinal permeability of rigosertib (ON 01910.Na, Estybon): correlation with systemic exposure J. Pharm. Pharmacol. 2013, 65, 960– 969 DOI: 10.1111/jphp.12057[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVCht77O&md5=e4b69c7551347aec1f8128561cc741fcDetermination of intestinal permeability of rigosertib (ON 01910.Na, Estybon): correlation with systemic exposureWhite, Michael P.; Babayeva, Mariana; Taft, David R.; Maniar, ManojJournal of Pharmacy and Pharmacology (2013), 65 (7), 960-969CODEN: JPPMAB; ISSN:0022-3573. (John Wiley & Sons Ltd.)Rigosertib (ON 01910.Na, Estybon) is a novel, anticancer agent undergoing phase 3 clin. trials for a lead indication against myelodysplastic syndromes (MDS). In this research, the permeability of rigosertib was evaluated using the in-situ perfused rat intestine (IPRI) model to support development of an oral formulation for rigosertib for treating cancer patients. Expts. (n = 6 per group) were conducted using male Sprague-Dawley rats. Studies evaluated permeability across various intestinal segments and assessed the dose-linearity of absorption over the entire intestinal length. Drug concns. in the portal and jugular vein were collected to correlate permeability parameters with presystemic and systemic exposure. Rigosertib permeability was highest in the jejunum, although parameter ests. indicated that rigosertib was a medium permeability compd. The compd. displayed nonlinear absorption in the IPRI model, suggesting a saturable transport process. Transport inhibition studies using Caco-2 cells demonstrated that rigosertib was a P-glycoprotein (P-gp) substrate. Abs. bioavailability of rigosertib (10 and 20 mg/kg, 1-h infusion) in rats was estd. to be 10-15%. However, the fraction absorbed in humans predicted from IPRI data (52%) was consistent with published clin. data for rigosertib (35% oral bioavailability). The results of this research indicated that rigosertib is a promising candidate for oral delivery. Further studies are needed to evaluate the potential impact of P-gp and other intestinal transporters on the oral absorption of this promising anticancer agent.
- 248Sero, V.; Tavanti, E.; Vella, S.; Hattinger, C. M.; Fanelli, M.; Michelacci, F.; Versteeg, R.; Valsasina, B.; Gudeman, B.; Picci, P.; Serra, M. Targeting polo-like kinase 1 by NMS-P937 in osteosarcoma cell lines inhibits tumor cell growth and partially overcomes drug resistance Invest. New Drugs 2014, 32, 1167– 1180 DOI: 10.1007/s10637-014-0158-6
- 249Nie, Z.; Feher, V.; Natala, S.; McBride, C.; Kiryanov, A.; Jones, B.; Lam, B.; Liu, Y.; Kaldor, S.; Stafford, J.; Hikami, K.; Uchiyama, N.; Kawamoto, T.; Hikichi, Y.; Matsumoto, S.; Amano, N.; Zhang, L.; Hosfield, D.; Skene, R.; Zou, H.; Cao, X.; Ichikawa, T. Discovery of TAK-960: an orally available small molecule inhibitor of polo-like kinase 1 (PLK1) Bioorg. Med. Chem. Lett. 2013, 23, 3662– 3666 DOI: 10.1016/j.bmcl.2013.02.083[Crossref], [PubMed], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnsVyksr0%253D&md5=25dca079405c47098fd261a77ceccf53Discovery of TAK-960: An orally available small molecule inhibitor of polo-like kinase 1 (PLK1)Nie, Zhe; Feher, Victoria; Natala, Srinivasa; McBride, Christopher; Kiryanov, Andre; Jones, Benjamin; Lam, Betty; Liu, Yan; Kaldor, Stephen; Stafford, Jeffrey; Hikami, Kouki; Uchiyama, Noriko; Kawamoto, Tomohiro; Hikichi, Yuichi; Matsumoto, Shin-ichi; Amano, Nobuyuki; Zhang, Lilly; Hosfield, David; Skene, Robert; Zou, Hua; Cao, Xiaodong; Ichikawa, TakashiBioorganic & Medicinal Chemistry Letters (2013), 23 (12), 3662-3666CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Using structure-based drug design, the authors identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960 (I). TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.
- 250Cheung, C. H. A.; Sarvagalla, S.; Lee, J. Y. C.; Huang, Y. C.; Coumar, M. S. Aurora kinase inhibitor patents and agents in clinical testing: an update (2011–2013) Expert Opin. Ther. Pat. 2014, 24, 1021– 1038 DOI: 10.1517/13543776.2014.931374[Crossref], [PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlKjtb3E&md5=20cc080521ab567ec3804e9beb5e505cAurora kinase inhibitor patents and agents in clinical testing: an update (2011 - 2013)Cheung, Chun Hei Antonio; Sarvagalla, Sailu; Lee, Jane Ying-Chieh; Huang, Yi-Chun; Coumar, Mohane SelvarajExpert Opinion on Therapeutic Patents (2014), 24 (9), 1021-1038CODEN: EOTPEG; ISSN:1354-3776. (Informa Healthcare)A review. Introduction: Aurora kinase A, B and C, members of serine/threonine kinase family, are key regulators of mitosis. As Aurora kinases are overexpressed in many of the human cancers, small-mol. inhibitors of Aurora kinase have emerged as a possible treatment option for cancer. Areas covered: In 2009 and 2011, the literature pertaining to Aurora kinase inhibitors and their patents was reviewed. Here, the aim is to update the information for Aurora kinase inhibitors in clin. trials and the patents filed between the years 2011 and 2013. Pubmed, Scopus, Scifinder, USPTO, EPO and www.clinicaltrials.gov databases were used for searching the literature and patents for Aurora kinase inhibitors. Expert opinion: Even though both Aurora sub-type selective as well as pan-selective inhibitors show preclin. and clin. efficacy, so far no Aurora kinase inhibitor has been approved for clin. use. Particularly, dose-limiting toxicity (neutropenia) is a key issue that needs to be addressed. Preliminary evidence suggests that the use of selective Aurora A inhibitors could avoid Aurora B-mediated neutropenia in clin. settings. Also, use of adjunctive agents such as granulocyte stimulating factor to overcome neutropenia assocd. with Aurora B inhibition could be an answer to overcome the toxicity and bring Aurora inhibitors to market in the future.
- 251Van Brocklyn, J. R.; Wojton, J.; Meisen, W. H.; Kellough, D. A.; Ecsedy, J. A.; Kaur, B.; Lehman, N. L. Aurora-A inhibition offers a novel therapy effective against intracranial glioblastoma Cancer Res. 2014, 74, 5364– 5370 DOI: 10.1158/0008-5472.CAN-14-0386
- 252Sathornsumetee, S.; Reardon, D. A.; Desjardins, A.; Quinn, J. A.; Vredenburgh, J. J.; Rich, J. N. Molecularly targeted therapy for malignant glioma Cancer 2007, 110, 13– 24 DOI: 10.1002/cncr.22741
- 253Mochly-Rosen, D.; Das, K.; Grimes, K. V. Protein kinase C, an elusive target? Nat. Rev. Drug Discovery 2012, 11, 937– 957 DOI: 10.1038/nrd3871
- 254(a) Kreisl, T. N.; Kotliarova, S.; Butman, J. A.; Albert, P. S.; Kim, L.; Musib, L.; Thornton, D.; Fine, H. A. A phase I/II trial of enzastaurin in pateints with recurrent high-grade gliomas Neuro-Oncology 2010, 12, 181– 189 DOI: 10.1093/neuonc/nop042(b) Wick, W.; Puduvalli, V. K.; Chamberlain, M. C.; van den Bent, M. J.; Carpentier, A. F.; Cher, L. M.; Mason, W.; Weller, M.; Hong, S.; Musib, L.; Liepa, A. M.; Thornton, D. E.; Fine, H. A. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma J. Clin. Oncol. 2010, 28, 1168– 1174 DOI: 10.1200/JCO.2009.23.2595[Crossref], [PubMed], [CAS], Google Scholar254bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXktF2ltb4%253D&md5=ac3cf8f3fc54dd6bbd6ef01866bbda0fPhase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastomaWick, Wolfgang; Puduvalli, Vinay K.; Chamberlain, Marc C.; van den Bent, Martin J.; Carpentier, Antoine F.; Cher, Lawrence M.; Mason, Warren; Weller, Michael; Hong, Shengyan; Musib, Luna; Liepa, Astra M.; Thornton, Donald E.; Fine, Howard A.Journal of Clinical Oncology (2010), 28 (7), 1168-1174CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Purpose: This phase III open-label study compared the efficacy and safety of enzastaurin vs. lomustine in patients with recurrent glioblastoma (WHO grade 4). Patients and Methods: Patients were randomly assigned 2:1 to receive 6-wk cycles of enzastaurin 500 mg/d (1,125-mg loading dose, day 1) or lomustine (100 to 130 mg/m2, day 1). Assuming a 45% improvement in progression-free survival (PFS), 397 patients were required to provide 80% power to achieve statistical significance at a one-sided level of .025. Results: Enrollment was terminated at 266 patients (enzastaurin, n = 174; lomustine, n = 92) after a planned interim anal. for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 mo; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 mo; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-mo PFS rate (P = .13) did not differ significantly between enzastaurin and lomustine, resp. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, resp. Time to deterioration of phys. and functional well-being and symptoms did not differ between arms (HR = 1.12; P = .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematol. toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P ≤ .001). Conclusion: Enzastaurin was well tolerated and had a better hematol. toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma.
- 255Gronberg, B. H.; Ciuleanu, T.; Flotten, O.; Knuuttila, A.; Abel, E.; Langer, S. W.; Krejcy, K.; Liepa, A. M.; Munoz, M.; Hahka-Kemppinen, M.; Sundstrom, S. A placebo-controlled, randomized phase II study of maintenance enzastaurin following whole brain radiation therapy in the treatment of brain metastases from lung cancer Lung Cancer 2012, 78, 63– 69 DOI: 10.1016/j.lungcan.2012.07.007
- 256Yasoshima, K.; Kuwabara, T.; Fuse, E.; Kuramitu, T.; Kurata, N.; Nishiie, H.; Oishi, T.; Kobayashi, H.; Kobayashi, S. Pharmacokinetics, distribution, metabolism and excretion of [3H]UCN-01 in rats and dogs after intravenous administration Cancer Chemother. Pharmacol. 2001, 47, 106– 112 DOI: 10.1007/s002800000213[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhsFSgtbc%253D&md5=7c92233a09c08beb24146c9d03a853c1Pharmacokinetics, distribution, metabolism and excretion of [3H]UCN-01 in rats and dogs after intravenous administrationYasoshima, Kenichi; Kuwabara, Takashi; Fuse, Eiichi; Kuramitu, Tomoko; Kurata, Noriaki; Nishiie, Hiroyoshi; Oishi, Takayoshi; Kobayashi, Hiroyuki; Kobayashi, SatoshiCancer Chemotherapy and Pharmacology (2001), 47 (2), 106-112CODEN: CCPHDZ; ISSN:0344-5704. (Springer-Verlag)Purpose: To evaluate the metabolic fate of UCN-01, a signal transduction inhibitor, blood and plasma concns., distribution, metab. and excretion were investigated in rats and dogs after i.v. administration of [3H]UCN-01. Methods: The radioactivity in plasma, blood and tissues was measured after i.v. administration of UCN-01. In addn., the radioactivity excreted in bile, urine and feces was also detd. Results: The radioactivity in rat and dog plasma disappeared triphasically with terminal half-lives of 21.3 and 27.2 h, resp. The ratios of the blood-to-plasma concns. ranged from 0.82 to 1.13 in rats and 0.81 to 1.73 in dogs. From 0.5 to 4 h after giving [3H]UCN-01 to rats, the radioactivity in all tissues except the brain and testes was higher than in plasma. The highest concn. was obsd. in the lungs followed by the liver and kidneys. The radioactivity was mainly excreted in feces, reaching 96.0% of the radioactivity dose in rats and 78.4% in dogs up to 168 h after injection. Since the biliary excreted radioactivity was 67.2% over 48 h in bile duct-cannulated rats, most of the radioactivity excreted in feces was from biliary radioactivity. There were several metabolites in bile samples, but little UCN-01. Conclusions: UCN-01 is mainly eliminated by the liver, and there are high concns. of radioactivity derived from [3H]UCN-01 in all tissues except the brain and testes.
- 257Budworth, J.; Davies, R.; Malkhandi, J.; Gant, T. W.; Ferry, D. R.; Gescher, A. Comparison of staurosporine and four analogues: their effects on growth, rhodamine 123 retention and binding to P-glycoprotein in multidrug-resistance MCF-7/Adr cells Br. J. Cancer 1996, 73, 1063– 1068 DOI: 10.1038/bjc.1996.205[Crossref], [PubMed], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjtlSiurw%253D&md5=7aa79db6a7c1e0793d938f69835b5d8cComparison of staurosporine and four analogs: Their effects on growth, rhodamine 123 retention and binding to P-glycoprotein in multidrug-resistant MCF-7/Adr cellsBudworth, J.; Davies, R.; Malkhandi, J.; Gant, T. W.; Ferry, D. R.; Gescher, A.British Journal of Cancer (1996), 73 (9), 1063-1068CODEN: BJCAAI; ISSN:0007-0920. (Stockton)The potent kinase inhibitor staurosporine and its protein kinase C (PKC)-selective analog CGP 41251 are known to sensitize cells with the multidrug resistance (MDR) phenotype mediated by P-glycoprotein (P-gp) to cytotoxic agents. Here four PKC-selective staurosporine congeners, CGP 41251, UCN-01, RO 31 8220 and GF 109203X, were compared with staurosporine in terms of their MDR-reversing properties and their susceptibility towards P-gp-mediated drug efflux from MCF-7/Adr cells. Staurosporine was the most potent and the bisindolylmaleimides RO 31 8220 and GF 109203X the least potent cytostatic agents. When compared with MCF-7 wild-type cells, MCF-7/Adr cells were resistant towards the growth-arresting properties of RO 31 8220 and UCN-01, with resistance ratios of 12.6 and 7.0 resp. This resistance could be substantially reduced by inclusion of the P-gp inhibitor reserpine. The ratios for GF 109203X, staurosporine and CGP 41251 were 1.2, 2.0 and 2.9 resp., and they were hardly affected by reserpine. These results suggest that RO 31 8220 and UCN-01 are avidly transported by P-gp but that the other compds. are not. Staurosporine and CGP 41251 at 10 and 20 nM, resp., decreased efflux of the P-gp probe rhodamine 123 (R123) from MCF-7/Adr cells, whereas RO 31 8220 and GF 109203X at 640 nM were inactive. CGP 41251 was the most effective and GF 109203X the least effective inhibitor of equil. binding of [3H]vinblastine to its specific binding sites, probably P-gp, in MCF-7/Adr cells. Overall, the results imply that for this class of compd. the structural properties that det. susceptibility towards P-gp-mediated substrate transport are complex. Comparison with ability to inhibit PKC suggests that the kinase inhibitors affect P-gp directly and not via inhibition of PKC. Among these compds. CGP 41251 was a very potent MDR-reversing agent with high affinity for P-gp and least affected by P-gp-mediated resistance, rendering it an attractive drug candidate for clin. development.
- 258Capdeville, R.; Buchdunger, E.; Zimmerman, J.; Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug Nat. Rev. Drug Discovery 2002, 1, 493– 502 DOI: 10.1038/nrd839[Crossref], [PubMed], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XkvFKlurY%253D&md5=c8f6b7a66f74b64f0dedb5e641097accGlivec (STI571, imatinib), a rationally developed, targeted anticancer drugCapdeville, Renaud; Buchdunger, Elisabeth; Zimmermann, Juerg; Matter, AlexNature Reviews Drug Discovery (2002), 1 (7), 493-502CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. In the early 1980s, it became apparent that the work of pioneers such as Robert Weinberg, Mariano Barbacid and many others in identifying cancer-causing genes in humans was opening the door to a new era in anticancer research. Motivated by this, and by dissatisfaction with the limited efficacy and tolerability of available anticancer modalities, a drug discovery program was initiated with the aim of rationally developing targeted anticancer therapies. Here, we describe how this program led to the discovery and continuing development of Glivec (Gleevec in the United States), the first selective tyrosine-kinase inhibitor to be approved for the treatment of a cancer.
- 259Quintas-Cardama, A.; Kantarjian, H. M.; Cortes, J. E. Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia Cancer Control 2009, 16, 122– 131
- 260Leis, J. F.; Stepan, D. E.; Curtin, P. T.; Ford, J. M.; Peng, B.; Schubach, S.; Druker, B. J.; Mariarz, R. T. Central nervous system failure in patients with chroinic mylogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571) Leuk. Lymphoma 2004, 45, 695– 698 DOI: 10.1080/10428190310001625728[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpvV2lsLg%253D&md5=f9279095aa2f10646f3a40e72a904170Central Nervous System Failure in Patients with Chronic Myelogenous Leukemia Lymphoid Blast Crisis and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Treated with Imatinib (STI-571)Leis, Jose; Stepan, Daniel; Curtin, Peter; Ford, John; Peng, Bin; Schubach, Susan; Druker, Brian; Maziarz, RichardLeukemia & Lymphoma (2004), 45 (4), 695-698CODEN: LELYEA; ISSN:1042-8194. (Taylor & Francis Ltd.)Isolated central nervous system (CNS) relapse occurred in 5 out of 24 patients (20.8%) with chronic myeloid leukemia (CML) lymphoid blast crisis (2), Philadelphia (Ph) chromosome pos. acute lymphoblastic leukemia (ALL) (2) or CML with biphenotypic markers (1) treated on imatinib mesylate (IM) protocols at our institution. CNS relapse occurred despite peripheral blood (5) and bone marrow (3) complete responses. Median time to CNS relapse was day 32 (range 23 to 100). This observation raised the possibility that IM may not penetrate into the CNS. Simultaneous plasma and cerebral spinal fluid (CSF) IM levels were detd. in four subsequent patients by liq. chromatog. and mass spectrophotometric assay. Levels of IM were found to be approx. two logs lower in CSF than in plasma (0.044 μg/mL (0.088±0.029 μM) vs. 3.27 μg/mL (6.54±0.93 μM)). CSF levels were substantially below the concn. required for inhibition of BCR-ABL and killing of cell lines in vitro. These results suggest that IM may not penetrate the intact blood/brain barrier and its implications are discussed.
- 261(a) Dai, H.; Marbach, P.; Lemaire, M.; Hayes, M.; Elmquist, W. F. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux J. Pharmacol. Exp. Ther. 2003, 304, 1085– 1092 DOI: 10.1124/jpet.102.045260[Crossref], [PubMed], [CAS], Google Scholar261ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXit1eisrs%253D&md5=c4f1082f27454e16635d768ce337ce7fDistribution of STI-571 to the brain is limited by P-glycoprotein-mediated effluxDai, Haiqing; Marbach, Peter; Lemaire, Michel; Hayes, Michael; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2003), 304 (3), 1085-1092CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)The adequate distribution of STI-571 (Gleevec) to the central nervous system (CNS) is crit. for its effective use in CNS tumors. P-glycoprotein-mediated efflux in the blood-brain barrier may play a role in the CNS delivery of this drug. Whether STI-571 is a substrate of P-glycoprotein was detd. by examg. the directional flux of [14C]STI-571 in parental and MDR1-transfected Madin-Darby canine kidney (MDCK) II epithelial cell monolayers. The basolateral-to-apical flux of STI-571 was 39-fold greater than the apical-to-basolateral flux in the MDR1-transfected cells and 8-fold greater in the parental cell monolayers. This difference in directional flux was significantly reduced by a specific P-glycoprotein inhibitor (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzo- suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (LY335979). The role of P-glycoprotein in the CNS distribution of STI-571 was examd. in vivo, using wild-type and mdr1a/b (-/-) knockout mice that were orally administered 25 mg/kg [14C]STI-571. In the wild-type mice, the brain-to-plasma STI-571 concn. ratio at all time points was low (1-3%); however, there was an 11-fold greater brain partitioning of STI-571 at 1 h postdose in the mdr1a/b (-/-) mice compared with the wild-type mice. When 12.5 mg/kg STI-571 was given i.v., the brain-to-plasma ratio of STI-571 in the mdr1a/b (-/-) mice was approx. 7-fold greater than that of wild-type mice up to 120 min postdose. These data indicate that STI-571 is a substrate of P-glycoprotein, and that the inhibition of P-glycoprotein affects the transport of STI-571 across MDCKII monolayers. Moreover, P-glycoprotein plays an important role in limiting the distribution of STI-571 to the CNS.(b) Breedveld, P.; Pluim, D.; Cipriani, G.; Wielinga, P.; van Tellingen, O.; Schinkel, A. H.; Schellens, J. H. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients Cancer Res. 2005, 65, 2577– 2582 DOI: 10.1158/0008-5472.CAN-04-2416(c) Rajappa, S.; Uppin, S. G.; Raghunadharao, D.; Rao, I. S.; Surath, A. Isolated central nervous system blast crisis in chronic myeloid leukemia Hematol. Oncol. 2004, 22, 179– 181 DOI: 10.1002/hon.737[Crossref], [PubMed], [CAS], Google Scholar261chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MvnsF2kug%253D%253D&md5=62855c254a97c7fc51884e685aa4bd39Isolated central nervous system blast crisis in chronic myeloid leukemiaRajappa Senthil; Uppin Shantveer G; Raghunadharao D; Rao I Satish; Surath AnjnaHematological oncology (2004), 22 (4), 179-81 ISSN:0278-0232.Chronic myeloid leukemia is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome, t(9:22). Extramedullary blast crisis is a rare event. Imatinib mesylate has become the treatment of choice, especially for patients for whom allogenic stem cell transplantation is not an option. Imatinib produces complete cytogenetic responses in excess of 80%. However, the penetration of the drug and its metabolites into the CNS (Central Nervous System) is poor. Hence for patients who are on prolonged imatinib therapy and continue to have complete cytogenetic responses, the central nervous system may become a sanctuary site. We report a patient who had a complete hematologic and cytogenetic response and presented with headache and vomiting. The MRI showed meningeal enhancement and the CSF (Cerebro Spinal Fluid) examination was positive for blasts. He was started on cranial radiotherapy and triple intrathecal chemotherapy. He showed good symptomatic improvement and cleared the blasts in the CSF. At the end of radiation, he was in complete hematological remission but had 50% marrow metaphases positive for Philadelphia chromosome. As he did not have a matched sibling donor, the dose of imatinib was increased to 600 mg daily. He continues to be in complete hematologic remission at the time of this report.(d) Neville, K.; Parise, R. A.; Thompson, P.; Aleksic, A.; Egorin, M. J.; Balis, F. M.; McGuffey, L.; McCully, C.; Berg, S. L.; Blaney, S. M. Plasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primates Clin. Cancer Res. 2004, 10, 2525– 2529 DOI: 10.1158/1078-0432.CCR-03-0155[Crossref], [PubMed], [CAS], Google Scholar261dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXivFSqsbo%253D&md5=1849626bb417a9aaa5b6b6e13c45bc5cPlasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primatesNeville, Kathleen; Parise, Robert A.; Thompson, Patrick; Aleksic, Alexander; Egorin, Merrill J.; Balis, Frank M.; McGuffey, Leticia; McCully, Cynthia; Berg, Stacey L.; Blaney, Susan M.Clinical Cancer Research (2004), 10 (7), 2525-2529CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Imatinib mesylate (Gleevec, Glivec, STI571, imatinib) is a potent tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors. The role of imatinib in the treatment of malignant gliomas and other solid tumors is being evaluated. We used a nonhuman primate model that is highly predictive of the cerebrospinal fluid penetration of drugs in humans to study the pharmacokinetics of imatinib in plasma and cerebrospinal fluid (CSF) after i.v. and p.o. administration. Imatinib, 15 mg/kg i.v. over 30 min (n = 3) or 30 mg/kg p.o. (n = 3), was administered to nonhuman primates. Imatinib was measured in serial samples of plasma and CSF using high-pressure liq. chromatog. with UV absorbance or mass spectroscopic detection. Pharmacokinetic parameters were estd. using model-independent methods. Peak plasma imatinib concns. ranged from 6.4 to 9.5 μM after i.v. dosing and 0.8 to 2.8 μM after p.o. dosing. The mean ±SD area under the plasma concn. vs. time curve was 2480 ±1340 μM·min and 1191 ±146 μM·min after i.v. and p.o. dosing, resp. The terminal half-life was 529 ±167 min after i.v. dosing and 266 ±88 min after p.o. dosing. After i.v. dosing the steady state vol. of distribution was 5.9 ±2.8 L/kg, and the total body clearance was 12 ±5 mL/min/kg. The mean peak CSF concn. was 0.25 ±0.07 μM after i.v. dosing and 0.07 ±0.04 μM after p.o. dosing. The mean CSF:plasma area under the plasma concn. vs. time curve ratio for all of the animals was 5% ±2%. There is limited penetration of imatinib into the CSF of nonhuman primates after i.v. and p.o. administration.
- 262Das, J.; Chen, P.; Norris, D.; Padmanabha, R.; Lin, J.; Moquin, R. V.; Shen, Z.; Cook, L. S.; Doweyko, A. M.; Pitt, S.; Pang, S.; Shen, D. R.; Fang, Q.; de Fex, H. F.; McIntyre, K. W.; Shuster, D. J.; Gillooly, K. M.; Behnia, K.; Schieven, G. L.; Wityak, J.; Barrish, J. C. 2-Aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor J. Med. Chem. 2006, 49, 6819– 6832 DOI: 10.1021/jm060727j
- 263Remsing Rix, L. L.; Rix, U.; Colinge, J.; Hantschel, O.; Bennett, K. L.; Stranzl, T.; Müller, A.; Baumgartner, C.; Valent, P.; Augustin, M.; Till, J. H.; Superti-Funga, G. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells Leukemia 2009, 23, 477– 485 DOI: 10.1038/leu.2008.334[Crossref], [PubMed], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXivVKhu7w%253D&md5=b0d56d468ef66ddc2a6f012d08f8c1a4Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cellsRemsing Rix, L. L.; Rix, U.; Colinge, J.; Hantschel, O.; Bennett, K. L.; Stranzl, T.; Mueller, A.; Baumgartner, C.; Valent, P.; Augustin, M.; Till, J. H.; Superti-Furga, G.Leukemia (2009), 23 (3), 477-485CODEN: LEUKED; ISSN:0887-6924. (Nature Publishing Group)The detailed mol. mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chem. proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells vs. the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clin. important mutant to be enzymically inhibited in the mid-nanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation. Leukemia (2009) 23, 477-485; doi:10.1038/leu.2008.334; published online 27 Nov. 2008.
- 264(a) Du, J.; Bernasconi, P.; Clauser, K. R.; Mani, D. R.; Finn, S. P.; Beroukhim, R.; Burns, M.; Julian, B.; Peng, X. P.; Hieronymus, H.; Maglathin, R. L.; Lewis, T. A.; Liau, L. M.; Nghiemphu, P.; Mellinghoff, I. K.; Louis, D. N.; Loda, M.; Carr, S. A.; Kung, A. L.; Golub, T. R. Bead-based kinase phosphorylation profiling identifies SRC as a therapeutic target in glioblastoma Nat. Biotechnol. 2009, 27, 77– 83 DOI: 10.1038/nbt.1513(b) Zhang, S.; Huang, W.-C.; Zhang, L.; Zhang, C.; Lowery, F. J.; Ding, Z.; Guo, H.; Wang, H.; Huang, S.; Sahin, A. A.; Aldape, K. D.; Steeg, P. S.; Yu, D. Src family kinases as novel therapeutic targets to treat breast cancer brain metastases Cancer Res. 2013, 73, 5764– 5774 DOI: 10.1158/0008-5472.CAN-12-1803
- 265Chen, Y.; Agarwal, S.; Shaik, N. M.; Chen, C.; Yang, Z.; Elmquist, W. F. P-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinib J. Pharmacol. Exp. Ther. 2009, 330, 956– 963 DOI: 10.1124/jpet.109.154781[Crossref], [PubMed], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVyitL3F&md5=2b43bf0468e6fea3a5aae1f84b3fb69dP-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinibChen, Ying; Agarwal, Sagar; Shaik, Naveed M.; Chen, Cliff; Yang, Zheng; Elmquist, William F.Journal of Pharmacology and Experimental Therapeutics (2009), 330 (3), 956-963CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)The novel tyrosine kinase inhibitor dasatinib (Sprycel; BMS-354825) is approved for use in imatinib (Gleevec; STI 571)-resistant or -intolerant chronic myelogenous leukemia and may be useful for other tumors in the central nervous system (CNS). The objective of this study was to investigate the role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in modulating the CNS penetration of dasatinib. Results from the in vitro studies indicate that cellular delivery of dasatinib is significantly limited by active efflux due to both P-gp and BCRP. Permeability studies indicated greater permeability in the basolateral-to-apical direction than in the apical-to-basolateral direction due to active efflux by P-gp or BCRP. Selective inhibitors of P-gp and BCRP, such as (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo-(a,e)cyclopropa(c) cycloheptan-6-yl)-α-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride (zosuquidar; LY335979) and 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12α-octahydropyrazino1',2':1,6pryrido3,4-bindol-3-yl)-propionic acid tert-Bu ester (Ko143), were able to restore the intracellular accumulation and abolish the directionality in net flux of dasatinib. In vivo brain distribution studies showed that the CNS distribution of dasatinib is limited, with the brain-to-plasma concn. ratios less than 0.12 in wild-type mice, which increased approx. 8-fold in Mdr1a/b(-/-) Bcrp1(-/-) mice. Dasatinib brain distribution was significantly increased in Mdr1a/b(-/-) mice and when wild-type mice were pretreated with LY335979. Simultaneous inhibition of P-gp and BCRP by elacridar [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] (GF120918) resulted in a 5-fold increase in brain concn. These in vitro and in vivo studies demonstrate that dasatinib is a substrate for the important efflux transporters p-glycoprotein and BCRP. These transport systems play a significant role in limiting the CNS delivery of dasatinib and may have direct implications in the treatment of primary and metastatic brain tumors.
- 266Porkka, K.; Koskenvesa, P.; Lundan, T.; Rimpilainen, J.; Mustjoki, S.; Smykla, R.; Wild, R.; Luo, R.; Arnan, M.; Brethon, B.; Eccersley, L.; Hjorth-Hansen, H.; Hoglund, M.; Klamova, H.; Knutsen, H.; Parikh, S.; Raffoux, E.; Gruber, F.; Brito-Babapulle, F.; Dombret, H.; Duarte, R. F.; Elonen, E.; Paquette, R.; Zwaan, C. M.; Lee, F. Y. F. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia Blood 2008, 112, 1005– 1012 DOI: 10.1182/blood-2008-02-140665[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpvVOksL0%253D&md5=2edc2781403f7d921ec732db2e9cd560Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome-positive leukemiaPorkka, Kimmo; Koskenvesa, Perttu; Lundan, Tuija; Rimpilainen, Johanna; Mustjoki, Satu; Smykla, Richard; Wild, Robert; Luo, Roger; Arnan, Montserrat; Brethon, Benoit; Eccersley, Lydia; Hjorth-Hansen, Henrik; Hoglund, Martin; Klamova, Hana; Knutsen, Havar; Parikh, Suhag; Raffoux, Emmanuel; Gruber, Franz; Brito-Babapulle, Finella; Dombret, Herve; Duarte, Rafael F.; Elonen, Erkki; Paquette, Ron; Zwaan, C. Michel; Lee, Francis Y. F.Blood (2008), 112 (4), 1005-1012CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-pos. (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasatinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclin. mouse model of intracranial Ph+ leukemia. Clin. dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclin. studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasatinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clin. significant, long-lasting responses, which were complete in 7 patients. In 3 addnl. patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compd. in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clin. activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.
- 267Hegedus, C.; Özvegy-Laczka, C.; Apati, A.; Magocsi, M.; Nemet, K.; Orfi, L.; Keri, G.; Katona, M.; Takats, Z.; Varadi, A.; Szakacs, G.; Sarkadi, B. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties Br. J. Pharmacol. 2009, 158, 1153– 1164 DOI: 10.1111/j.1476-5381.2009.00383.x[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVSks7fM&md5=5f1105ff91e04f6f1b865591aeb0fcabInteraction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: Implications for altered anti-cancer effects and pharmacological propertiesHegedus, C.; Ozvegy-Laczka, C.; Apati, A.; Magocsi, M.; Nemet, K.; Orfi, L.; Keri, G.; Katona, M.; Takats, Z.; Varadi, A.; Szakacs, G.; Sarkadi, B.British Journal of Pharmacology (2009), 158 (4), 1153-1164CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)Background and purpose: ABC multidrug transporters (MDR-ABC proteins) cause multiple drug resistance in cancer and may be involved in the decreased anti-cancer efficiency and modified pharmacol. properties of novel specifically targeted agents. It has been documented that ABCB1 and ABCG2 interact with several first-generation, small-mol., tyrosine kinase inhibitors (TKIs), including the Bcr-Abl fusion kinase inhibitor imatinib, used for the treatment of chronic myeloid leukemia. Here, we have investigated the specific interaction of these transporters with nilotinib, dasatinib and bosutinib, three clin. used, second-generation inhibitors of the Bcr-Abl tyrosine kinase activity. Exptl. approach: MDR-ABC transporter function was screened in both membrane- and cell-based (K562 cells) systems. Cytotoxicity measurements in Bcr-Abl-pos. model cells were coupled with direct detn. of intracellular TKI concns. by high-pressure liq. chromatog.-mass spectrometry and anal. of the pattern of Bcr-Abl phosphorylation. Transporter function in membranes was assessed by ATPase activity. Key results: Nilotinib and dasatinib were high-affinity substrates of ABCG2, and this protein mediated an effective resistance in cancer cells against these compds. Nilotinib and dasatinib also interacted with ABCB1, but this transporter provided resistance only against dasatinib. Neither ABCB1 nor ABCG2 induced resistance to bosutinib. At relatively higher concns., however, each TKI inhibited both transporters. Conclusions and implications: A combination of in vitro assays may provide valuable preclin. information for the applicability of novel targeted anti-cancer TKIs, even in multidrug-resistant cancer. The pattern of MDR-ABC transporter-TKI interactions may also help to understand the general pharmacokinetics and toxicities of new TKIs.
- 268Atilla, E.; Ataca, P.; Ozyurek, E.; Erden, I.; Gurman, G. Successful bosutinib experience in an elderly acute lymphoblastic leukemia patient with suspected central nervous system involvement transformed from chronic myeloid leukemia Case Rep. Hematol. 2015, 2015, 689423 DOI: 10.1155/2015/689423[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28rkt1Squw%253D%253D&md5=55f21453f302c1d787e85e2951f18e5aSuccessful Bosutinib Experience in an Elderly Acute Lymphoblastic Leukemia Patient with Suspected Central Nervous System Involvement Transformed from Chronic Myeloid LeukemiaAtilla Erden; Ataca Pinar; Gurman Gunhan; Ozyurek Elif; Erden IlhanCase reports in hematology (2015), 2015 (), 689423 ISSN:2090-6560.Managing the blast phase in chronic myeloid leukemia (CML) is challenging because limited data are available for elderly patients. The involvement of the central nervous system (CNS) increases the risk of a poor prognosis. Here, we present an elderly blast phase CML patient with suspected CNS involvement who was successfully treated with bosutinib.
- 269Taylor, J. W.; Dietrich, J.; Gerstner, E. R.; Norden, A. D.; Rinne, M. L.; Cahill, D. P.; Stemmer-Rachamimov, A.; Wen, P. Y.; Betensky, R. A.; Giorgio, D. H.; Snodgrass, K.; Randall, A. E.; Batchelor, T. T.; Chi, A. S. Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma J. Neuro-Oncol. 2015, 121, 557– 563 DOI: 10.1007/s11060-014-1667-z[Crossref], [PubMed], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVWksLfJ&md5=6ad16c8f43cfd988185b43b7d5121656Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastomaTaylor, Jennie W.; Dietrich, Jorg; Gerstner, Elizabeth R.; Norden, Andrew D.; Rinne, Mikael L.; Cahill, Daniel P.; Stemmer-Rachamimov, Anat; Wen, Patrick Y.; Betensky, Rebecca A.; Giorgio, Diana H.; Snodgrass, Kellis; Randall, Alison E.; Batchelor, Tracy T.; Chi, Andrew S.Journal of Neuro-Oncology (2015), 121 (3), 557-563CODEN: JNODD2; ISSN:0167-594X. (Springer)Tumor cell infiltration is a major mechanism of treatment escape in glioblastoma. Src is an intracellular tyrosine kinase that mediates tumor cell motility and invasiveness. We evaluated the efficacy and safety of bosutinib, a tyrosine kinase inhibitor that potently inhibits Src and Abl, in patients with recurrent glioblastoma. In this two-arm study, patients with histol. confirmed recurrent glioblastoma and ≤2 relapses, not previously treated with anti-vascular endothelial growth factor (VEGF) therapy, were administered oral bosutinib 400 mg daily. Arm A planned for 6 patients who were candidates for surgical resection to be given bosutinib for 7-9 days prior to resection. Arm B was a two-stage design phase 2 trial targeting 30 patients. The primary endpoint was progression-free survival at 6 mo (PFS6) in Arm B. After 9 patients enrolled onto stage 1 of Arm B, 9 (100 %) patients progressed within 6 mo. Therefore, the study met the pre-specified criteria for early closure and both Arms were closed. In Arm B, Median PFS was 7.71 wk and median OS was 50 wk. Best objective response was stable disease in one patient (11.1 %). Seven patients (77.8 %) had treatment-related AEs of any grade and 2 (22.2 %) were grade ≥3. Arm A was closed after 2 patients enrolled. Src activation was evident in all archival tumor samples. Bosutinib monotherapy does not appear to be effective in recurrent glioblastoma. However, Src remains a potential target based on its upregulation in tumor samples and role in glioma invasion.
- 270(a) Kosztyu, P.; Dolezel, P.; Mlejnek, P. Can P-glycoprotein mediate resistance to nilotinib in human leukaemia cells? Pharmacol. Res. 2013, 67, 79– 83 DOI: 10.1016/j.phrs.2012.10.012[Crossref], [PubMed], [CAS], Google Scholar270ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVCktbzM&md5=2eb3d2796c8f45edaffb64a858a000b2Can P-glycoprotein mediate resistance to nilotinib in human leukaemia cells?Kosztyu, Petr; Dolezel, Petr; Mlejnek, PetrPharmacological Research (2013), 67 (1), 79-83CODEN: PHMREP; ISSN:1043-6618. (Elsevier Ltd.)The effect of P-glycoprotein (P-gp, ABCB1, MDR1) expression on cell resistance to nilotinib was studied in human leukemia cells. We used K562/Dox cells overexpressing P-gp and their variants (subclones) with a gradually decreased P-gp expression. These subclones were established by stable transfection of K562/Dox cells with a plasmid vector expressing shRNA targeting the ABCB1 gene. Functional anal. of P-gp using a specific fluorescent probe indicated gradually decreased dye efflux which was proportional to the P-gp expression. We obsd. that K562/Dox cells overexpressing P-gp contained a significantly reduced intracellular level of nilotinib when compared to their counter partner K562 cells, which do not express P-gp. This effect was accompanied by a decreased sensitivity of the K562/Dox cells to nilotinib. Importantly, cells with downregulated expression of P-gp gradually lost their ability to decrease the intracellular level of nilotinib although they still significantly decreased the intracellular level of daunorubicin (DNR). Accordingly, cells with the reduced expression of P-gp concomitantly failed to provide resistance to nilotinib, however, they exhibited a significant resistance to DNR. Taken together, we demonstrated that the conclusion as to whether P-gp is involved in nilotinib resistance or not strongly depends on its expression at protein level.(b) Yamakawa, Y.; Hamada, A.; Uchida, T.; Sato, D.; Yuki, M.; Hayashi, M.; Kawaguchi, T.; Saito, H. Distinct interaction of nilotinib and imatinib with P-glycoprotein in intracellular accumulation and cytotoxicity in CML cell line K562 cells Biol. Pharm. Bull. 2014, 37, 1330– 1335 DOI: 10.1248/bpb.b14-00254[Crossref], [PubMed], [CAS], Google Scholar270bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslWitbfK&md5=af5c25b1d5551f3e3c36d768d677f9c9Distinct interaction of nilotinib and imatinib with P-glycoprotein in intracellular accumulation and cytotoxicity in CML cell line K562 cellsYamakawa, Yuji; Hamada, Akinobu; Uchida, Takashi; Sato, Daisuke; Yuki, Misato; Hayashi, Masahiro; Kawaguchi, Tatsuya; Saito, HideyukiBiological & Pharmaceutical Bulletin (2014), 37 (8), 1330-1335CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for first-line chronic myeloid leukemia (CML) treatment. The improved clin. response of nilotinib over that of the first generation TKI, imatinib, has been thought to be a result of its high potency of inhibition of BCR-ABL kinase. This study aimed to characterize differences between nilotinib and imatinib in the intracellular accumulation and cytotoxic effect on the CML cell line K562. Accumulation of nilotinib in K562 cells was from 4.7- to 9.0-fold higher than that of imatinib. The cytotoxic effect of nilotinib on K562 cells was 14.2-fold higher than that of imatinib. Inhibition expts. in K562 cells, and examn. of the cellular uptake using influx transporter-transfected human embryonic kidney (HEK) 293 cells, suggested that the influx transporters OCT1 and OATP1A2, which have been reported to mediate accumulation of imatinib in CML cells, contributed little to the uptake of nilotinib. Nilotinib was found to accumulate in imatinib-resistant K562 (K562/IM) cells overexpressing the efflux transporter P-glycoprotein (P-gp), although cytotoxic assays showed that K562/IM cells displayed 20000-fold greater resistance to nilotinib over the parent K562 cells. In conclusion, the present findings suggest that intracellular accumulation of nilotinib in CML cells contributes to its clin. response and efficacy in CML patients. Although nilotinib has been reported to be effective against imatinib-resistant ABL kinase mutants, the drug could not overcome imatinib resistance acquired by P-gp-overexpression. These results imply that classification of mechanisms of drug resistance is important for suitable strategies to treat imatinib-resistant CML patients.
- 271Weisberg, E.; Manley, P. W.; Breitenstein, W.; Brüggen, J.; Cowan-jacob, S. W.; Ray, A.; Huntly, B.; Fabbro, D.; Fendrich, G.; Hall-Meyers, E.; Kung, A. L.; Mestan, J.; Daley, G. Q.; Callahan, L.; Catley, L.; Cavazza, C.; Mohammed, A.; Neuberg, D.; Wright, R. D.; Gilliand, D. G.; Griffin, J. D. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl Cancer Cell 2005, 7, 129– 141 DOI: 10.1016/j.ccr.2005.01.007[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXitFygu7o%253D&md5=d28e1a54b982951f8d3e6ef1d2d3b2ebCharacterization of AMN107, a selective inhibitor of native and mutant Bcr-AblWeisberg, Ellen; Manley, Paul W.; Breitenstein, Werner; Brueggen, Josef; Cowan-Jacob, Sandra W.; Ray, Arghya; Huntly, Brian; Fabbro, Doriano; Fendrich, Gabriele; Hall-Meyers, Elizabeth; Kung, Andrew L.; Mestan, Juergen; Daley, George Q.; Callahan, Linda; Catley, Laurie; Cavazza, Cara; Mohammed, Azam; Neuberg, Donna; Wright, Renee D.; Gilliland, D. Gary; Griffin, James D.Cancer Cell (2005), 7 (2), 129-141CODEN: CCAECI; ISSN:1535-6108. (Cell Press)The Bcr-Abl tyrosine kinase oncogene causes chronic myelogenous leukemia (CML) and Philadelphia chromosome-pos. (Ph+) acute lymphoblastic leukemia (ALL). We describe a novel selective inhibitor of Bcr-Abl, AMN107 (IC50 < 30 nM), which is significantly more potent than imatinib, and active against a no. of imatinib-resistant Bcr-Abl mutants. Crystallog. anal. of Abl-AMN107 complexes provides a structural explanation for the differential activity of AMN107 and imatinib against imatinib-resistant Bcr-Abl. Consistent with its in vitro and pharmacokinetic profile, AMN107 prolonged survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolonged survival in imatinib-resistant CML mouse models. AMN107 is a promising new inhibitor for the therapy of CML and Ph+ ALL.
- 272Reinwald, M.; Schleyer, E.; Kiewe, P.; Blau, I. W.; Burmeister, T.; Pursche, S.; Neumann, M.; Notter, M.; Thiel, E.; Hofmann, W.-K.; Kolb, H.-J.; Burdach, S.; Bender, H.-U. Efficacy and pharmacologic data of second-generation tyrosine kinase inhibitor nilotinib in BCR-ABL-positive leukemia patients with central nervous system relapse after allogeneic stem cell transplantation BioMed Res. Int. 2014, 2014, 637059 DOI: 10.1155/2014/637059
- 273Lonskaya, I.; Hebron, M. L.; Selby, S. T.; Turner, R. S.; Moussa, C. E.-H. Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in alzheimer’s disease models Neuroscience 2015, 304, 316– 327 DOI: 10.1016/j.neuroscience.2015.07.070
For example see the following and references therein:
[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1ygs7bO&md5=ada20cd34de6ec95abd50ff55426ba7cNilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer's disease modelsLonskaya, I.; Hebron, M. L.; Selby, S. T.; Turner, R. S.; Moussa, C. E.-H.Neuroscience (Amsterdam, Netherlands) (2015), 304 (), 316-327CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)Alzheimer's disease (AD) brains exhibit plaques and tangles in assocn. with inflammation. The non-receptor tyrosine kinase Abl is linked to neuro-inflammation in AD. Abl inhibition by nilotinib or bosutinib facilitates amyloid clearance and may decrease inflammation. Transgenic mice that express Dutch, Iowa and Swedish APP mutations (TgAPP) and display progressive Aβ plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to det. pre-plaque effects on systemic and CNS inflammation using milliplex ELISA. Plaque Aβ was detected at 4 mo in TgAPP and pre-plaque intracellular Aβ accumulation (2.5 mo) was assocd. with changes of cytokines and chemokines prior to detection of glial changes. Plaque formation correlated with increased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1α, IL-1β) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, Vascular Endothelial Growth Factor (VEGF) and IFN-γ. An inverse relationship of chemokines was obsd. as CCL2 and CCL5 were lower than WT mice at 2 mo and significantly increased after plaque appearance, while sol. CX3CL1 decreased. A change in glial profile was only robustly detected at 6 mo in Tg-APP mice and TKIs reduced astrocyte and dendritic cell no. with no effects on microglia, suggesting alteration of brain immunity. Nilotinib decreased blood and brain cytokines and chemokines and increased CX3CL1. Bosutinib increased brain and blood IL-10 and CX3CL1, suggesting a protective role for sol. CX3CL1. Taken together these data suggest that TKIs regulate systemic and CNS immunity and may be useful treatments in early AD through dual effects on amyloid clearance and immune modulation. - 274Huang, W.-S.; Metcalf, C. A.; Sundaramoorthi, R.; Wang, Y.; Zou, D.; Thomas, R. M.; Zhu, X.; Cai, L.; Wen, D.; Liu, S.; Romero, J.; Qi, J.; Chen, I.; Banda, G.; Lentini, S. P.; Das, S.; Xu, Q.; Keats, J.; Wang, F.; Wardwell, S.; Ning, Y.; Snodgrass, J. T.; Broudy, M. I.; Russian, K.; Zhou, T.; Commodore, L.; Narasimhan, N. I.; Mohemmad, Q. K.; Iuliucci, J.; Rivera, V. M.; Dalgarno, D. C.; Sawyer, T. K.; Clackson, T.; Shakespeare, W. C. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)-methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-Abelson (BCR-ABL) kinase including the T315I gatekeeper mutant J. Med. Chem. 2010, 53, 4701– 4719 DOI: 10.1021/jm100395q[ACS Full Text], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmslels7s%253D&md5=0dcd7b4ff31164b1d9883e897b7058ffDiscovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-[4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl]benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper MutantHuang, Wei-Sheng; Metcalf, Chester A.; Sundaramoorthi, Raji; Wang, Yihan; Zou, Dong; Thomas, R. Mathew; Zhu, Xiaotian; Cai, Lisi; Wen, David; Liu, Shuangying; Romero, Jan; Qi, Jiwei; Chen, Ingrid; Banda, Geetha; Lentini, Scott P.; Das, Sasmita; Xu, Qihong; Keats, Jeff; Wang, Frank; Wardwell, Scott; Ning, Yaoyu; Snodgrass, Joseph T.; Broudy, Marc I.; Russian, Karin; Zhou, Tianjun; Commodore, Lois; Narasimhan, Narayana I.; Mohemmad, Qurish K.; Iuliucci, John; Rivera, Victor M.; Dalgarno, David C.; Sawyer, Tomi K.; Clackson, Tim; Shakespeare, William C.Journal of Medicinal Chemistry (2010), 53 (12), 4701-4719CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate benzamide I (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC50s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of I significantly prolonged survival of mice injected i.v. with BCR-ABLT315I expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of I to be an effective treatment for CML, including patients refractory to all currently approved therapies.
- 275Laramy, J. K.; Parrish, K. E.; Zhang, S.; Bakken, K. K.; Carlson, B. L.; Mladek, A. C.; Ma, D. J.; Sarkaria, J. N.; Elmquist, W. F. Brain distribution of ponatinib, a multi-kinase inhibitor: implications for the treatment of malignant brain tumors Am. Assoc. Pharm. Sci. 2015, W4339
- 276Niwa, T.; Asaki, T.; Kimura, S. NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor Anal. Chem. Insights 2007, 2, 93– 106[Crossref], [PubMed], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MrktFSnsA%253D%253D&md5=5c846df1ba45ec0d09d3a0d2cb8ee20eNS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitorNiwa Tomoko; Asaki Tetsuo; Kimura ShinyaAnalytical chemistry insights (2007), 2 (), 93-106 ISSN:.Protein kinases catalyze the transfer of the gamma-phosphoryl group of adenosine triphosphate (ATP) to the hydroxyl groups of protein side chains, and they play critical roles in regulating cellular signal transduction and other biochemical processes. They are attractive targets for today's drug discovery and development, and many pharmaceutical companies are intensively developing various kinds of protein kinase inhibitors. A good example is the recent success with the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (Gleevec) in the treatment of chronic myeloid leukemia. Though imatinib has dramatically improved the treatment of Bcr-Abl-positive chronic myeloid leukemia, resistance is often found in patients with advanced-stage disease. Several mechanisms have been proposed to explain this resistance, including point mutations within the Abl kinase domain, amplification of the bcr-abl gene, overexpression of the corresponding mRNA, increased drug efflux mediated by P-glycoprotein, and activation of the Src-family kinase (SFK) Lyn. We set out to develop a novel drug whose affinity for Abl is higher than that of imatinib and whose specificity in inhibiting Lyn is higher than that of SFK/Abl inhibitors such as dasatinib (Sprycel) or bosutinib (SKI-606). Our work has led to the development of NS-187 (INNO-406), a novel Abl/Lyn dual tyrosine kinase inhibitor with clinical prospects. To provide an overview of how a selective kinase inhibitor has been developed, this review presents chemical-modification studies carried out with the guidance of molecular modeling, the structural basis for the high potency and selectivity of NS-187 based on the X-ray structure of the NS-187/Abl complex, and the biological profiling of NS-187, including site-directed mutagenesis experiments.
- 277Portnow, J.; Badie, B.; Markel, S.; Liu, A.; D’Apuzzo, M.; Frankel, P.; Jandial, R.; Synold, T. W. A neuropharmocokinetic assessment of bafetinib, a second generation dual BCR-Abl/Lyn tyrosine kinase inhibitor, in patients with recurrent high-grade gliomas Eur. J. Cancer 2013, 49, 1634– 1640 DOI: 10.1016/j.ejca.2013.01.001
- 278Yokota, A.; Kimura, S.; Masuda, S.; Ashihara, E.; Kuroda, J.; Sato, K.; Kamitsuji, Y.; Kawata, E.; Deguchi, Y.; Urasaki, Y.; Terui, Y.; Ruthardt, M.; Ueda, T.; Hatake, K.; Inui, K.; Maekawa, T. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity Blood 2007, 109, 306– 314 DOI: 10.1182/blood-2006-03-013250
- 279Hennequin, L. F.; Allen, J.; Breed, J.; Curwen, J.; Fennell, M.; Green, T. P.; Lambert-van der Brempt, C.; Morgentin, R.; Norman, R. A.; Olivier, A.; Otterbein, L.; Ple, P. A.; Warin, N.; Costello, G. N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor J. Med. Chem. 2006, 49, 6465– 6488 DOI: 10.1021/jm060434q
- 280Kaufman, A. C.; Salazar, S. V.; Haas, L. T.; Yang, J.; Kostylev, M. A.; Jeng, A. T.; Robinson, S. A.; Gunther, E. C.; van Dyck, C. H.; Nygaard, H. B.; Strittmatter, S. M. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice Ann. Neurol. 2015, 77, 953– 971 DOI: 10.1002/ana.24394[Crossref], [PubMed], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpt1yitro%253D&md5=dbefcbdecd53b505110110f41e6174bdFyn inhibition rescues established memory and synapse loss in Alzheimer miceKaufman, Adam C.; Salazar, Santiago V.; Haas, Laura T.; Yang, Jinhee; Kostylev, Mikhail A.; Jeng, Amanda T.; Robinson, Sophie A.; Gunther, Erik C.; van Dyck, Christopher H.; Nygaard, Haakon B.; Strittmatter, Stephen M.Annals of Neurology (2015), 77 (6), 953-971CODEN: ANNED3; ISSN:0364-5134. (John Wiley & Sons, Inc.)Objective: Currently no effective disease-modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathol. triggered by amyloid-β oligomers (Aβo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncol. compd., AZD0530, for AD. Methods: The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aβo signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild-type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metab., synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochem. and by immunoblotting. Results : AZD0530 potently inhibits Fyn and prevents both Asso-induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 wk of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Ass metab. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. Interpretation: Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse d. loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD.
- 281Nygaard, H. B.; Wagner, A. F.; Bowen, G. S.; Good, S. P.; MacAvoy, M. G.; Strittmatter, K. A.; Kaufman, A. C.; Rosenberg, B. J.; Sekine-Konno, T.; Varma, P.; Chen, K.; Koleske, A. J.; Reiman, E. M.; Strittmatter, S. M.; van Dyck, C. H. A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer’s disease Alzheimer's Res. Ther. 2015, 7, 35 DOI: 10.1186/s13195-015-0119-0[Crossref], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MjktlSjtA%253D%253D&md5=fda8573af23de7ef7468acbfd5879094A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's diseaseNygaard Haakon B; Wagner Allison F; Bowen Garrett S; Good Susan P; MacAvoy Martha G; Strittmatter Kurt A; Kaufman Adam C; Rosenberg Brian J; Sekine-Konno Tomoko; Varma Pradeep; Chen Kewei; Reiman Eric M; Koleske Anthony J; Strittmatter Stephen M; van Dyck Christopher HAlzheimer's research & therapy (2015), 7 (1), 35 ISSN:.INTRODUCTION: Despite significant progress, a disease-modifying therapy for Alzheimer's disease (AD) has not yet been developed. Recent findings implicate soluble oligomeric amyloid beta as the most relevant protein conformation in AD pathogenesis. We recently described a signaling cascade whereby oligomeric amyloid beta binds to cellular prion protein on the neuronal cell surface, activating intracellular Fyn kinase to mediate synaptotoxicity. Fyn kinase has been implicated in AD pathophysiology both in in vitro models and in human subjects, and is a promising new therapeutic target for AD. Herein, we present a Phase Ib trial of the repurposed investigational drug AZD0530, a Src family kinase inhibitor specific for Fyn and Src kinase, for the treatment of patients with mild-to-moderate AD. METHODS: The study was a 4-week Phase Ib multiple ascending dose, randomized, double-blind, placebo-controlled trial of AZD0530 in AD patients with Mini-Mental State Examination (MMSE) scores ranging from 16 to 26. A total of 24 subjects were recruited in three sequential groups, with each randomized to receive oral AZD0530 at doses of 50 mg, 100 mg, 125 mg, or placebo daily for 4 weeks. The drug:placebo ratio was 3:1. Primary endpoints were safety, tolerability, and cerebrospinal fluid (CSF) penetration of AZD0530. Secondary endpoints included changes in clinical efficacy measures (Alzheimer's Disease Assessment Scale - cognitive subscale, MMSE, Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory, Neuropsychiatric Inventory, and Clinical Dementia Rating Scale - Sum of Boxes) and regional cerebral glucose metabolism measured by fluorodeoxyglucose positron emission tomography. RESULTS: AZD0530 was generally safe and well tolerated across doses. One subject receiving 125 mg of AZD0530 was discontinued from the study due to the development of congestive heart failure and atypical pneumonia, which were considered possibly related to the study drug. Plasma/CSF ratio of AZD0530 was 0.4. The 100 mg and 125 mg doses achieved CSF drug levels corresponding to brain levels that rescued memory deficits in transgenic mouse models. One-month treatment with AZD0530 had no significant effect on clinical efficacy measures or regional cerebral glucose metabolism. CONCLUSIONS: AZD0530 is reasonably safe and well tolerated in patients with mild-to-moderate AD, achieving substantial central nervous system penetration with oral dosing at 100-125 mg. Targeting Fyn kinase may be a promising therapeutic approach in AD, and a larger Phase IIa clinical trial of AZD0530 for the treatment of patients with AD has recently launched. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01864655. Registered 12 June 2014.
- 282(a) Abounader, R.; Laterra, J. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis Neuro-Oncology 2005, 7, 436– 451 DOI: 10.1215/S1152851705000050(b) Zhang, Y.; Farenholtz, K. E.; Yang, Y.; Guessous, F.; diPierro, C. G.; Calvert, V. S.; Deng, J.; Schiff, D.; Xin, W.; Lee, J. K.; Purow, B.; Christensen, J.; Petricoin, E.; Abounader, R. Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition Clin. Cancer Res. 2013, 19, 1433– 1444 DOI: 10.1158/1078-0432.CCR-12-2832[Crossref], [PubMed], [CAS], Google Scholar282bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktFKktro%253D&md5=182ec75be957278f9f46eb2013f702fcHepatocyte Growth Factor Sensitizes Brain Tumors to c-MET Kinase InhibitionZhang, Ying; Farenholtz, Kaitlyn E.; Yang, Yanzhi; Guessous, Fadila; diPierro, Charles G.; Calvert, Valerie S.; Deng, Jianghong; Schiff, David; Xin, Wenjun; Lee, Jae K.; Purow, Benjamin; Christensen, James; Petricoin, Emanuel; Abounader, RogerClinical Cancer Research (2013), 19 (6), 1433-1444CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clin. applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not-well-known mol. determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors. Exptl. Design: We investigated the mol. factors and pathway activation signatures that det. sensitivity to c-MET inhibitors in a panel of glioblastoma and medulloblastoma cells, glioblastoma stem cells, and established cell line-derived xenografts using functional assays, reverse protein microarrays, and in vivo tumor vol. measurements, but validation with animal survival analyses remains to be done. We also explored new approaches for improving the efficacy of the inhibitors in vitro and in vivo. Results: We found that HGF coexpression is a key predictor of response to c-MET inhibition among the examd. factors and identified an ERK/JAK/p53 pathway activation signature that differentiates c-MET inhibition in responsive and nonresponsive cells. Surprisingly, we also found that short pretreatment of cells and tumors with exogenous HGF moderately but statistically significantly enhanced the antitumor effects of c-MET inhibition. We obsd. a similar ligand-induced sensitization effect to an EGF receptor small-mol. kinase inhibitor. Conclusions: These findings allow the identification of a subset of patients that will be responsive to c-MET inhibition and propose ligand pretreatment as a potential new strategy for improving the anticancer efficacy of RTK inhibitors. Clin Cancer Res; 19(6); 1433-44. ©2013 AACR.
- 283Qian, F.; Engst, S.; Yamaguchi, K.; Yu, P.; Won, K. A.; Mock, L.; Lou, T.; Tan, J.; Li, C.; Tam, D.; Lougheed, J.; Yakes, F. M.; Bentzien, F.; Xu, W.; Zaks, T.; Wooster, R.; Greshock, J.; Joly, A. H. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases Cancer Res. 2009, 69, 8009– 8016 DOI: 10.1158/0008-5472.CAN-08-4889[Crossref], [PubMed], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1ynurbF&md5=f3bf5b432ee42b164d23b690828e3c78Inhibition of Tumor Cell Growth, Invasion, and Metastasis by EXEL-2880 (XL880, GSK1363089), a Novel Inhibitor of HGF and VEGF Receptor Tyrosine KinasesQian, Fawn; Engst, Stefan; Yamaguchi, Kyoko; Yu, Peiwen; Won, Kwang-Ai; Mock, Lillian; Lou, Tracy; Tan, Jenny; Li, Connie; Tam, Danny; Lougheed, Julie; Yakes, F. Michael; Bentzien, Frauke; Xu, Wei; Zaks, Tal; Wooster, Richard; Greshock, Joel; Joly, Alison H.Cancer Research (2009), 69 (20), 8009-8016CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a wide variety of human malignancies. Vascular endothelial growth factor (VEGF) receptors are expressed on the surface of vascular endothelial cells and cooperate with Met to induce tumor invasion and vascularization. EXEL-2880 (XL880, GSK1363089) is a small-mol. kinase inhibitor that targets members of the HGF and VEGF receptor tyrosine kinase families, with addnl. inhibitory activity toward KIT, Flt-3, platelet-derived growth factor receptor β, and Tie-2. Binding of EXEL-2880 to Met and VEGF receptor 2 (KDR) is characterized by a very slow off-rate, consistent with X-ray crystallog. data showing that the inhibitor is deeply bound in the Met kinase active site cleft. EXEL-2880 inhibits cellular HGF-induced Met phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and prevents both HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells. In addn., EXEL-2880 prevents anchorage-independent proliferation of tumor cells under both normoxic and hypoxic conditions. In vivo, these effects produce significant dose-dependent inhibition of tumor burden in an exptl. model of lung metastasis. Collectively, these data indicate that EXEL-2880 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion and angiogenesis mediated by HGF and VEGF receptors.
- 284Faria, C. C.; Golbourn, B. J.; Dubuc, A. M.; Remke, M.; Diaz, R. J.; Agnihotri, S.; Luck, A.; Sabha, N.; Olsen, S.; Wu, X.; Garzia, L.; Ramaswamy, V.; Mack, S. C.; Wang, X.; Leadley, M.; Reynaud, D.; Ermini, L.; Post, M.; Northcott, P. A.; Pfister, S. M.; Croul, S. E.; Kool, M.; Korshunov, A.; Smith, C. A.; Taylor, M. D.; Rutka, J. T. Foretinib is effective for metastatic sonic hedgehog medulloblastoma Cancer Res. 2015, 75, 134– 146 DOI: 10.1158/0008-5472.CAN-13-3629
- 285Buchanan, S. G.; Hendle, J.; Lee, P. S.; Smith, C. R.; Bounaud, P. Y.; Jessen, K. A.; Tang, C. M.; Huser, N. H.; Felce, J. D.; Froning, K. J.; Peterman, M. C.; Aubol, B. E.; Gessert, S. F.; Sauder, J. M.; Schwinn, K. D.; Russell, M.; Rooney, I. A.; Adams, J.; Leon, B. C.; Do, T. H.; Blaney, J. M.; Sprengeler, P. A.; Thompson, D. A.; Smyth, L.; Pelletier, L. A.; Atwell, S.; Holme, K.; Wasserman, S. R.; Emtage, S.; Burley, S. K.; Reich, S. H. SGX is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo Mol. Cancer Ther. 2009, 8, 3181– 3190 DOI: 10.1158/1535-7163.MCT-09-0477[Crossref], [PubMed], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFCitbzI&md5=7410ae811f0bf2d3298691ed34d35878SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivoBuchanan, Sean G.; Hendle, Jorg; Lee, Patrick S.; Smith, Christopher R.; Bounaud, Pierre-Yves; Jessen, Katti A.; Tang, Crystal M.; Huser, Nanni H.; Felce, Jeremy D.; Froning, Karen J.; Peterman, Marshall C.; Aubol, Brandon E.; Gessert, Steve F.; Sauder, J. Michael; Schwinn, Kenneth D.; Russell, Marijane; Rooney, Isabelle A.; Adams, Jason; Leon, Barbara C.; Do, Tuan H.; Blaney, Jeff M.; Sprengeler, Paul A.; Thompson, Devon A.; Smyth, Lydia; Pelletier, Laura A.; Atwell, Shane; Holme, Kevin; Wasserman, Stephen R.; Emtage, Spencer; Burley, Stephen K.; Reich, Siegfried H.Molecular Cancer Therapeutics (2009), 8 (12), 3181-3190CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)The MET receptor tyrosine kinase has emerged as an important target for the development of novel cancer therapeutics. Activation of MET by mutation or gene amplification has been linked to kidney, gastric, and lung cancers. In other cancers, such as glioblastoma, autocrine activation of MET has been demonstrated. Several classes of ATP-competitive inhibitor have been described, which inhibit MET but also other kinases. Here, we describe SGX523, a novel, ATP-competitive kinase inhibitor remarkable for its exquisite selectivity for MET. SGX523 potently inhibited MET with an IC50 of 4 nmol/L and is >1000-fold selective vs. the >200-fold selectivity of other protein kinases tested in biochem. assays. Crystallog. study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity. SGX523 inhibited MET-mediated signaling, cell proliferation, and cell migration at nanomolar concns. but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concns. SGX523 inhibition of MET in vivo was assocd. with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. Our results show that SGX523 is the most selective inhibitor of MET catalytic activity described to date and is thus a useful tool to investigate the role of MET kinase in cancer without the confounding effects of promiscuous protein kinase inhibition.
- 286Guessous, F.; Zhang, Y.; diPierro, C.; Marcinkiewicz, L.; Sarkaria, J.; Schiff, D.; Buchanan, S.; Abounader, R. An orally bioavailable c-Met kinase inhibitor potently inhibits brain tumor malignancy and growth Anti-Cancer Agents Med. Chem. 2010, 10, 28– 35 DOI: 10.2174/1871520611009010028
- 287(a) Underiner, T. L.; Herbertz, T.; Miknyoczki, S. J. Disovery of small molecule c-Met inhibitors: evolution and profiles of clinical candidates Anti-Cancer Agents Med. Chem. 2010, 10, 7– 27 DOI: 10.2174/1871520611009010007(b) Burbridge, M. F.; Bossard, C. J.; Saunier, C.; Fejes, I.; Bruno, I.; Bruno, A.; Leonce, S.; Ferry, G.; Da Violante, G.; Bouzom, F.; Cattan, V.; Jacquet-Bescond, A.; Comoglio, P. M.; Lockhart, B. P.; Boutin, J. A.; Cordi, A.; Ortuno, J. C.; Pierre, A.; Hickman, J. A.; Cruzalegui, F. H.; Depil, S. S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab Mol. Cancer Ther. 2013, 12, 1749– 1762 DOI: 10.1158/1535-7163.MCT-13-0075[Crossref], [PubMed], [CAS], Google Scholar287bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtl2lur7O&md5=a53009f7a7b0601cf45598ca5b8775c2S49076 Is a Novel Kinase Inhibitor of MET, AXL, and FGFR with Strong Preclinical Activity Alone and in Association with BevacizumabBurbridge, Mike F.; Bossard, Celine J.; Saunier, Carine; Fejes, Imre; Bruno, Alain; Leonce, Stephane; Ferry, Gilles; Da Violante, Georges; Bouzom, Francois; Cattan, Valerie; Jacquet-Bescond, Anne; Comoglio, Paolo M.; Lockhart, Brian P.; Boutin, Jean A.; Cordi, Alex; Ortuno, Jean-Claude; Pierre, Alain; Hickman, John A.; Cruzalegui, Francisco H.; Depil, StephaneMolecular Cancer Therapeutics (2013), 12 (9), 1749-1762CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been assocd. with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclin. characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclin. studies showing a favorable and novel pharmacol. profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749-62. ©2013 AACR.
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Literature related to the following c-Met inhibitors was reviewed in an effort to identify any information regarding potential for CNS penetration, including whether the molecules are P-gp substrates: LY2801653, PF-04217903, golvatinib, JNJ-58877605, PHA-66752, tivantinib.
There is no corresponding record for this reference. - 289(a) Gutenberg, A.; Brück, W.; Buchfelder, M.; Ludwig, H. C. Expression of tyrosine kinases FAK and Pyk2 in 331 human astrocytomas Acta Neuropathol. 2004, 108, 224– 230 DOI: 10.1007/s00401-004-0886-3[Crossref], [PubMed], [CAS], Google Scholar289ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmt1Krur8%253D&md5=05f4ecbba6b2aabbef6fd97445398d27Expression of tyrosine kinases FAK and Pyk2 in 331 human astrocytomasGutenberg, A.; Brueck, W.; Buchfelder, M.; Ludwig, H. C.Acta Neuropathologica (2004), 108 (3), 224-230CODEN: ANPTAL; ISSN:0001-6322. (Springer GmbH)The progression of malignancy from astrocytomas to glioblastomas remains clin. as well as histopathol. unpredictable. The focal adhesion kinase (FAK) and the proline-rich Tyr kinase (Pyk2) show a high expression in glioma cell lines and have an influence on increased cell proliferation and migration of glioma cells in vitro and in vivo. The aim of this study was to correlate the coexpression of FAK and Pyk2 to the WHO grade of malignancy in human astrocytomas. Immunohistochem. staining scores of FAK and Pyk2 were analyzed in 331 astrocytomas and correlated to each other and to the WHO grade. Significant coexpression of FAK and Pyk2 in astrocytomas was demonstrated. Pyk2 expression occurred much more frequently and with higher expression scores within the different WHO grades. Beyond this, a significant correlation between the WHO grade of malignancy of astrocytomas and the expression of FAK, as well as of Pyk2, was detected. This connection and the roles of these 2 Tyr kinases in the progression of tumors should be confirmed by further studies.(b) Rolon-Reyes, K.; Kucheryavykh, Y. V.; Cubano, L. A.; Inyushin, M.; Skatchkov, S. N.; Eaton, M. J.; Harrison, J. K.; Kucheryavykh, L. Y. Microglia activate migration of glioma cells through a Pyk2 intracellular pathway PLoS One 2015, 10, e0131059 DOI: 10.1371/journal.pone.0131059
- 290Sulzmaier, F. J.; Jean, C.; Schlaepfer, D. D. FAK in cancer: mechanistic findings and clinical applications Nat. Rev. Cancer 2014, 14, 598– 610 DOI: 10.1038/nrc3792[Crossref], [PubMed], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht12nu7vJ&md5=f498bcf7af890d2f92eda68e42f979d1FAK in cancer: mechanistic findings and clinical applicationsSulzmaier, Florian J.; Jean, Christine; Schlaepfer, David D.Nature Reviews Cancer (2014), 14 (9), 598-610CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. FAK promotes tumor progression and metastasis through effects on cancer cells, as well as stromal cells of the tumor microenvironment. The kinase-dependent and kinase-independent functions of FAK control cell movement, invasion, survival, gene expression and cancer stem cell self-renewal. Small mol. FAK inhibitors decrease tumor growth and metastasis in several preclin. models and have initial clin. activity in patients with limited adverse events. In this Review, we discuss FAK signalling effects on both tumor and stromal cell biol. that provide rationale and support for future therapeutic opportunities.
- 291Luzzio, M.; Autry, C.; Berliner, M.; Coleman, K.; Cooper, B.; Desrosiers, E.; Emerson, E.; Griffor, M.; Hulford, C.; Jani, J.; Kath, J.; LaGreca, S.; Lin, J.; Lorenzen, M.; Marr, E.; Martinez-Alsina, L.; Patel, N.; Richter, D.; Ung, E.; Vajdos, F.; Wessel, M.; Whalen, P.; Yao, L.; Roberts, W. Abstract 5432: Design, synthesis, activity and properties of selective focal adhesion kinase inhibitors which are suitable for advanced preclinical evaluation: the discovery of PF-562271 Cancer Res. 2007, 67 (Suppl.) 5432
- 292Xu, Q.; Pachter, J. A.; Tam, W. Methods and compositions for treating abnormal cell growth (e.g., cancer) using FAK inhibitor and a MEK inhibitor. WO Patent WO2015120289 A1, 2015.
- 293Schlaepfer, D. Method of promoting apoptosis and inhibiting metastasis. WO Patent WO2011019943 A1, 2011.
- 294Auger, K. R.; Peddareddigari, V. G. R. Combinations. WO Patent WO2014059095 A1, 2014.
- 295Mulholland, P.; Williams, M.; Arkenau, H. T.; Fleming, R.; Tolson, J.; Yan, L.; Zhang, J.; Swartz, L.; Singh, R.; Auger, K.; Lenox, L.; Cox, D.; Plisson, C.; Saleem, A.; Searle, G.; Blagden, S. ATNT 06. Evaluation of the safety of GSK2256098 and pharmacokinetics of 11C-GSK2256098 in patients with recurrent glioblastoma by positron emission tomography (PET) imaging Neuro-Oncology 2015, 17 (Suppl. 5) v11 DOI: 10.1093/neuonc/nov205.06
- 296(a) Han, J.; Alvarez-Breckenridge, C. A.; Wang, Q. E.; Yu, J. TGF-b signaling and its targeting for glioma treatment Am. J. Cancer Res. 2015, 5, 945– 955[PubMed], [CAS], Google Scholar296ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MbgslCisw%253D%253D&md5=6722803b2cc34a4e7343f91c0da9664cTGF-β signaling and its targeting for glioma treatmentHan Jianfeng; Yu Jianhua; Alvarez-Breckenridge Christopher A; Wang Qi-EnAmerican journal of cancer research (2015), 5 (3), 945-55 ISSN:.Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine, secreted by a variety of cells including immune cells, tumor cells, and stromal cells. TGF-β signaling is dysregulated in cancer patients, and this aberrant signaling at least in part contributes to initiation and progression of many cancers including glioma. The dysregulated signaling components provide molecular targets for the treatment of glioma. In this article, we review TGF-β signaling and its targeting in glioma.(b) Luwor, R. B.; Kaye, A. H.; Zhu, H. J. Transforming growth factor-beta (TGF-b) and brain tumors J. Clin. Neurosci. 2008, 15, 845– 855 DOI: 10.1016/j.jocn.2008.01.003[Crossref], [PubMed], [CAS], Google Scholar296bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnvVOntrw%253D&md5=1e135fed7c8de3aa3a0d4f8ec24b39f5Transforming growth factor-beta (TGF-β) and brain tumoursLuwor, Rodney B.; Kaye, Andrew H.; Zhu, Hong-JianJournal of Clinical Neuroscience (2008), 15 (8), 845-855CODEN: JCNUE6; ISSN:0967-5868. (Elsevier B.V.)A review. Since its discovery in the late 1970s considerable research has linked transforming growth factor-beta (TGF-β) to several human diseases such as fibrosis, auto-immunity and cancer. TGF-β acts initially as a growth inhibitory factor in early stages of tumor development. In contrast, as tumors evolve, they develop mechanisms to evade the growth-regulatory effects of TGF-β, resulting in greater tumor invasiveness, increased metastatic potential and inhibition of surrounding immune responses. However, although extensively studied, the mol. mechanisms that trigger tumor cells to "switch" from TGF-β-inhibited to TGF-β-promoted are still not fully understood. Contradictory studies that demonstrate opposite cellular effects mediated by TGF-β are abundant throughout the literature. This review summarizes the current mol. mechanisms involved in the tumor suppressive and tumor progressive characteristics of TGF-β in brain tumors. Potential therapeutic agents that target TGF-β and related proteins being evaluated against brain tumors is also discussed.
- 297Herbertz, S.; Sawyer, J. S.; Stauber, A. J.; Gueorguieva, I.; Driscoll, K. E.; Estrem, S. T.; Cleverly, A. L.; Desaiah, D.; Guba, S. C.; Benhadji, K. A.; Slapak, C. A.; Lahn, M. M. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta singaling pathway Drug Des., Dev. Ther. 2015, 9, 4479– 4499 DOI: 10.2147/DDDT.S86621[Crossref], [PubMed], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC287nsVChuw%253D%253D&md5=37fa07dc9996dc98fafdab1a658f0d96Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathwayHerbertz Stephan; Sawyer J Scott; Stauber Anja J; Estrem Shawn T; Desaiah Durisala; Guba Susan C; Benhadji Karim A; Slapak Christopher A; Lahn Michael M; Gueorguieva Ivelina; Cleverly Ann L; Driscoll Kyla EDrug design, development and therapy (2015), 9 (), 4479-99 ISSN:.Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.
- 298Herzog, S.; Fink, M. A.; Weitmann, K.; Friedel, C.; Hadlich, S.; Langner, S.; Kindermann, K.; Holm, T.; Bohm, A.; Eskilsson, E.; Miletic, H.; Hildner, M.; Fritsch, M.; Vogelgesang, S.; Havemann, C.; Ritter, C. A.; Meyer zu Schwabedissen, H. E.; Rauch, B.; Hoffmann, W.; Kroemer, H. K.; Schroeder, H.; Bien-Moller, S. Pim1 kinase is upregulated in glioblastoma multiforme and mediates tumor cell survival Neuro-Oncology 2015, 17, 223– 242 DOI: 10.1093/neuonc/nou216
- 299Chen, L. S.; Redkar, S.; Bearss, D.; Wierda, W. G.; Gandhi, V. Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells Blood 2009, 114, 4150– 4157 DOI: 10.1182/blood-2009-03-212852[Crossref], [PubMed], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVGku7vL&md5=3ef35f4c41c753a9c1c8245a6392bce2Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cellsChen, Lisa S.; Redkar, Sanjeev; Bearss, David; Wierda, William G.; Gandhi, VarshaBlood (2009), 114 (19), 4150-4157CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)Pim kinases are involved in B-cell development and are overexpressed in B-cell chronic lymphocytic leukemia (CLL). We hypothesized that Pim kinase inhibition would affect B-cell survival. Identified from a screen of imidazo[1,2-b]pyridazine compds., SGI-1776 inhibits Pim-1, Pim-2, and Pim-3. Treatment of CLL cells with SGI-1776 results in a concn.-dependent induction of apoptosis. To elucidate its mechanism of action, we evaluated the effect of SGI-1776 on Pim kinase function. Unlike in replicating cells, phosphorylation of traditional Pim-1 kinase targets, phospho-Bad (Ser112) and histone H3 (Ser10), and cell-cycle proteins were unaffected by SGI-1776, suggesting an alternative mechanism in CLL. Protein levels of total c-Myc as well as phospho-c-Myc(Ser62), a Pim-1 target site, were decreased after SGI-1776 treatment. Levels of antiapoptotic proteins Bcl-2, Bcl-XL, XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant redn. in Mcl-1 was obsd. that was not caused by caspase-mediated cleavage of Mcl-1 protein. The mechanism of decline in Mcl-1 was at the RNA level and was correlated with inhibition of global RNA synthesis. Consistent with a decline in new RNA synthesis, MCL-1 transcript levels were decreased after treatment with SGI-1776. These data suggest that SGI-1776 induces apoptosis in CLL and that the mechanism involves Mcl-1 redn.
- 300Burger, M. T.; Nishiguchi, G.; Han, W.; Lan, J.; Simmons, R.; Atallah, G.; Ding, Y.; Tamez, V.; Zhang, Y.; Mathur, M.; Muller, K.; Bellamacina, C.; Lindvall, M. K.; Zang, R.; Huh, K.; Feucht, P.; Zavorotinskaya, T.; Dai, Y.; Basham, S.; Chan, J.; Ginn, E.; Aycinena, A.; Holash, J.; Castillo, J.; Langowski, J. L.; Wang, Y.; Chen, M. Y.; Lambert, A.; Fritsch, C.; Kauffmann, A.; Pfister, E.; Vanasse, K. G.; Garcia, P. D. Identification of N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a potent and selective proviral insertion site of moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitor in clinical trials for hematological malignancies J. Med. Chem. 2015, 58, 8373– 8386 DOI: 10.1021/acs.jmedchem.5b01275
- 301Keeton, E. K.; McEachern, K.; Dillman, K. S.; Palakurthi, S.; Cao, Y.; Grondine, M. R.; Kaur, S.; Wang, S.; Chen, Y.; Wu, A.; Shen, M.; Gibbons, F. D.; Lamb, M. L.; Zheng, X.; Stone, R. M.; DeAngelo, D. J.; Platanias, L. C.; Dakin, L. A.; Chen, H.; Lyne, P. D.; Huszar, D. AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia Blood 2014, 123, 905– 913 DOI: 10.1182/blood-2013-04-495366[Crossref], [PubMed], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisFaqs7o%253D&md5=4277790b53c9064787cbd68c159e552bAZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemiaKeeton, Erika K.; McEachern, Kristen; Dillman, Keith S.; Palakurthi, Sangeetha; Cao, Yichen; Grondine, Michael R.; Kaur, Surinder; Wang, Suping; Chen, Yuching; Wu, Allan; Shen, Minhui; Gibbson, Francis D.; Lamb, Michelle L.; Zheng, Xiaolan; Stone, Richard M.; DeAngelo, Daniel J.; Platanias, Leonidas C.; Dakin, Les A.; Chen, Huawei; Lyne, Paul D.; Huszar, DennisBlood (2014), 123 (6), 905-913CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)Upregulation of Pim kinases is obsd. in several types of leukemias and lymphomas. Pim-1, -2, and -3 promote cell proliferation and survival downstream of cytokine and growth factor signaling pathways. AZD1208 is a potent, highly selective, and orally available Pim kinase inhibitor that effectively inhibits all three isoforms at <5 nM or <150 nM in enzyme and cell assays, resp. AZD1208 inhibited the growth of 5 of 14 acute myeloid leukemia (AML) cell lines tested, and sensitivity correlates with Pim-1 expression and STAT5 activation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells, accompanied by a dose-dependent redn. in phosphorylation of Bcl-2 antagonist of cell death, 4EBP1, p70S6K, and S6, as well as increases in cleaved caspase 3 and p27. Inhibition of p4EBP1 and p-p70S6K and suppression of translation are the most representative effects of Pim inhibition in sensitive AML cell lines. AZD1208 inhibits the growth of MOLM-16 and KG-1a xenograft tumors in vivo with a clear pharmacodynamic-pharmacokinetic relationship. AZD1208 also potently inhibits colony growth and Pim signaling substrates in primary AML cells from bone marrow that are Flt3 wild-type or Flt3 internal tandem duplication mutant. These results underscore the therapeutic potential of Pim kinase inhibition for the treatment of AML.
- 302Pan, Z.; Scheerens, H.; Li, S. J.; Schultz, B. E.; Sprengeler, P. A.; Burrill, L. C.; Mendonca, R. V.; Sweeney, M. D.; Scott, K. C. K.; Grothaus, P. G.; Jeffery, D. A.; Spoerke, J. M.; Honigberg, L. A.; Young, P. R.; Dalrymple, S. A.; Palmer, J. T. Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase ChemMedChem 2007, 2, 58– 61 DOI: 10.1002/cmdc.200600221[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsVWjsbg%253D&md5=023ba8bca9942ad0127d7cf32293e9d2Discovery of selective irreversible inhibitors for bruton's tyrosine kinasePan, Zhengying; Scheerens, Heleen; Li, Shyr-Jiann; Schultz, Brian E.; Sprengeler, Paul A.; Burrill, L. Chuck; Mendonca, Rohan V.; Sweeney, Michael D.; Scott, Keana C. K.; Grothaus, Paul G.; Jeffery, Douglas A.; Spoerke, Jill M.; Honigberg, Lee A.; Young, Peter R.; Dalrymple, Stacie A.; Palmer, James T.ChemMedChem (2007), 2 (1), 58-61CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Synthesis and pharmacol. evaluation of a series of peptidomimetic quinoline derivs. was undertaken to evaluate their efficacy in acting as selective irreversible inhibitors of Bruton's tyrosine kinase (Btk). With the relative scarcity of knowledge on the inhibition of Btk it is crucial to discover a potent and selective tool compd. for this kinase. Herein is described the discovery of selective irreversible Btk inhibitors and their efficacy in a mouse RA model.
- 303Bernard, S.; Goldwirt, L.; Amorim, S.; Brice, P.; Bnere, J.; de Kerviller, E.; Mourah, S.; Sauvageon, H.; Thieblemont, C. Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse Blood 2015, 126, 1695– 1698 DOI: 10.1182/blood-2015-05-647834
- 304205552 Clinical Pharmacology Review. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205552Orig1s000ClinPharmR.pdf (accessed June 12, 2016) .
- 305(a) Biddlestone-Thorpe, L.; Sajjad, M.; Rosenberg, E.; Beckta, J. M.; Valerie, N. C. K.; Tokarz, M.; Adams, B. R.; Wagner, A. F.; Khalil, A.; Gilfor, D.; Golding, S. E.; Deb, S.; Temesi, D. G.; Lau, A.; O’Connor, M. J.; Choe, K. S.; Parada, L. F.; Lim, S. K.; Mukhopadhyay, N. D.; Valerie, K. ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation Clin. Cancer Res. 2013, 19, 3189– 3200 DOI: 10.1158/1078-0432.CCR-12-3408[Crossref], [PubMed], [CAS], Google Scholar305ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpsVynsL4%253D&md5=b77a60ce3d07e969f3cacb897676e6f8ATM Kinase Inhibition Preferentially Sensitizes p53-Mutant Glioma to Ionizing RadiationBiddlestone-Thorpe, Laura; Sajjad, Muhammad; Rosenberg, Elizabeth; Beckta, Jason M.; Valerie, Nicholas C. K.; Tokarz, Mary; Adams, Bret R.; Wagner, Alison F.; Khalil, Ashraf; Gilfor, Donna; Golding, Sarah E.; Deb, Sumitra; Temesi, David G.; Lau, Alan; O'Connor, Mark J.; Choe, Kevin S.; Parada, Luis F.; Lim, Sang Kyun; Mukhopadhyay, Nitai D.; Valerie, KristofferClinical Cancer Research (2013), 19 (12), 3189-3200CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival of only 12 to 15 mo. Current std. treatment consists of surgery followed by chemoradiation. The poor survival of patients with GBM is due to aggressive tumor invasiveness, an inability to remove all tumor tissue, and an innate tumor chemo- and radioresistance. Ataxia-telangiectasia mutated (ATM) is an excellent target for radiosensitizing GBM because of its crit. role in regulating the DNA damage response and p53, among other cellular processes. As a first step toward this goal, we recently showed that the novel ATM kinase inhibitor KU-60019 reduced migration, invasion, and growth, and potently radiosensitized human glioma cells in vitro. Exptl. Design: Using orthotopic xenograft models of GBM, we now show that KU-60019 is also an effective radiosensitizer in vivo. Human glioma cells expressing reporter genes for monitoring tumor growth and dispersal were grown intracranially, and KU-60019 was administered intratumorally by convection-enhanced delivery or osmotic pump. Results: Our results show that the combined effect of KU-60019 and radiation significantly increased survival of mice 2- to 3-fold over controls. Importantly, we show that glioma with mutant p53 is much more sensitive to KU-60019 radiosensitization than genetically matched wild-type glioma. Conclusions: Taken together, our results suggest that an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers. Clin Cancer Res; 19(12); 3189-200. ©2013 AACR.(b) Nadkarni, A.; Shrivastav, M.; Mladek, A. C.; Schwingler, P. M.; Grogan, P. T.; Chen, J.; Sarkaria, J. N. ATM inhibitor Ku-55993 increases the TMZ responsiveness of only inherently TMZ sensitive GBM cells J. Neuro-Oncol. 2012, 110, 349– 357 DOI: 10.1007/s11060-012-0979-0[Crossref], [PubMed], [CAS], Google Scholar305bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs12rs7bI&md5=be2aa0965dab757cd6d61cb83143c905ATM inhibitor KU-55933 increases the TMZ responsiveness of only inherently TMZ sensitive GBM cellsNadkarni, Aditi; Shrivastav, Meena; Mladek, Ann C.; Schwingler, Paul M.; Grogan, Patrick T.; Chen, Junjie; Sarkaria, Jann N.Journal of Neuro-Oncology (2012), 110 (3), 349-357CODEN: JNODD2; ISSN:0167-594X. (Springer)Ataxia telangiectasia mutated (ATM) kinase is crit. in sensing and repairing DNA double-stranded breaks (DSBs) such as those induced by temozolomide (TMZ). ATM deficiency increases TMZ sensitivity, which suggests that ATM inhibitors may be effective TMZ sensitizing agents. In this study, the TMZ sensitizing effects of 2 ATM specific inhibitors were studied in established and xenograft-derived glioblastoma (GBM) lines that are inherently sensitive to TMZ and deriv. TMZ-resistant lines. In parental U251 and U87 glioma lines, the addn. of KU-55933 to TMZ significantly increased cell killing compared to TMZ alone [U251 survival: 0.004 ± 0.0015 vs. 0.08 ± 0.01 (p < 0.001), resp., and U87 survival: 0.02 ± 0.005 vs. 0.04 ± 0.002 (p < 0.001), resp.] and also elevated the fraction of cells arrested in G2/M [U251 G2/M fraction: 61.8 ± 1.1 % vs. 35 ± 0.8 % (p < 0.001), resp., and U87 G2/M fraction 25 ± 0.2 % vs.18.6 ± 0.4 % (p < 0.001), resp.]. In contrast, KU-55933 did not sensitize the resistant lines to TMZ, and neither TMZ alone or combined with KU-55933 induced a G2/M arrest. While KU-55933 did not enhance TMZ induced Chk1/Chk2 activation, it increased TMZ-induced residual γ-H2AX foci in the parental cells but not in the TMZ resistant cells. Similar sensitization was obsd. with either KU-55933 or CP-466722 combined with TMZ in GBM12 xenograft line but not in GBM12TMZ, which is resistant to TMZ due to MGMT overexpression. These findings are consistent with a model where ATM inhibition suppresses the repair of TMZ-induced DSBs in inherently TMZ-sensitive tumor lines, which suggests an ATM inhibitor potentially could be deployed with an improvement in the therapeutic window when combined with TMZ.
- 306Linger, R. M. A.; Keating, A. K.; Earp, H. Sh.; Graham, D. K. Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors Expert Opin. Ther. Targets 2010, 14, 1073– 1090 DOI: 10.1517/14728222.2010.515980[Crossref], [PubMed], [CAS], Google Scholar306https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFOktL3I&md5=078559de448e07d9360eaff2b167ddefTaking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumorsLinger, Rachel M. A.; Keating, Amy K.; Earp, H. Shelton; Graham, Douglas K.Expert Opinion on Therapeutic Targets (2010), 14 (10), 1073-1090CODEN: EOTTAO; ISSN:1472-8222. (Informa Healthcare)A review. Importance of the field: Axl and/or Mer expression correlates with poor prognosis in several cancers. Until recently, the role of these receptor tyrosine kinases (RTKs) in development and progression of cancer remained unexplained. Studies demonstrating that Axl and Mer contribute to cell survival, migration, invasion, metastasis and chemosensitivity justify further investigation of Axl and Mer as novel therapeutic targets in cancer. Areas covered in this review: Axl and Mer signaling pathways in cancer cells are summarized and evidence validating these RTKs as therapeutic targets in glioblastoma multiforme, NSCLC, and breast cancer is examd. A discussion of Axl and/or Mer inhibitors in development is provided.What the reader will gain: Potential toxicities assocd. with Axl or Mer inhibition are addressed. We propose that the probable action of Mer and Axl inhibitors on cells within the tumor microenvironment will provide a therapeutic opportunity to target both tumor cells and the stromal components that facilitate disease progression. Take home message: Axl and Mer mediate multiple oncogenic phenotypes and activation of these RTKs constitutes a mechanism of chemoresistance in a variety of solid tumors. Targeted inhibition of these RTKs may be effective as anti-tumor and/or anti-metastatic therapy, particularly if combined with std. cytotoxic therapies.
- 307Joshi, A. D.; Loilome, W.; Siu, I.-M.; Tyler, B.; Gallia, G. L.; Riggins, G. J. Evaluation of tyrosine kinase inhibitor combinations for glioblastoma therapy PLoS One 2012, 7, e44372 DOI: 10.1371/journal.pone.0044372
As an example of the potential importance of inhibiting multiple kinases:
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See Supporting Information for details of individual inhibitors.
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Supporting Information
ARTICLE SECTIONSThe Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00618.
Calculated physicochemical properties of FDA approved kinase inhibitors and of discussed inhibitors that are capable of penetrating the BBB or have limited CNS penetration (PDF)
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